Kidney tumor - cysts, children, adult benign

Definition: total of 3 or more renal cysts in both kidneys, in patients with end stage renal disease; may be related to uremia, not dialysis; apparently unrelated to etiology of renal disease

Epidemiology: seen in 7-22% of uremic patients not on dialysis, 40% on dialysis for 3 years, 90% on dialysis for 10 years; more common in men; also occurs in children and young adults on dialysis (Pediatr Nephrol 1997;11:447)

Pathophysiology: cysts may form due to obstruction by oxalate crystals, fibrosis or hyperplasia

Clinical: increased (7-50x) risk of renal cell carcinoma (7% @ 10 years), but death is rare (Clin Nephrol 2003;59:153)

Case reports: 36 year old man on CAPD for 6 years (Nephrol Dial Transplant 2002;17:500)

Gross: moderately enlarged bilateral kidneys with cysts up to 2 cm in cortex and medulla containing clear fluid, often with calcium oxalate crystals; papillary hyperplasia common

Gross images: associated with chronic dialysis; renal transplant 12 years prior; with central scar

Micro: cysts lined by flattened to hyperplastic cuboidal or columnar epithelium; may have atypical papillary projections

Micro images: various images; multiple thin walled cysts lined by flattened epithelial cells; fig 2-atypical papillary hyperplasia, fig 1 & 3-associated carcinomas; fig c: non-tumorous stroma adjacent to cyst

Cytogenetics: atypical epithelial proliferations associated with gains of #7, #12, #17, #20, Y, suggesting they represent early neoplasms (Hum Path 2002;33:761)

Differential diagnosis: autosomal dominant polycystic kidney disease - positive family history, extremely large kidneys with cystic contour

References: eMedicine, J Clin Pathol 1977;30:868, Eur Radiol 2000;10:1716

Autosomal dominant (adult) polycystic kidney disease - Kidney-tumor chapter

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Definition: autosomal dominant disorder due to PKD1, PDK2 and PKD3 mutations with almost complete penetrance; have bilateral large kidneys composed of masses of cysts

Epidemiology: 1-2/1000 live births, no gender preference; also associated with TSC2/PKD1 contiguous gene syndrome (Am J Surg Pathol 2002;26:198)

Pathophysiology: multiple expanding bilateral cysts compress and obstruct only part of normal nephron, so normal renal function until age 30-49 years; cause unknown

Clinical: causes 10% of chronic renal failure requiring transplantation or dialysis; associated with von Meyenburg complexes in liver (97%, Mod Path 1996;9:233), hepatic cysts (40-88%), berry aneurysms (10-30%, cause death in 4-10%), mitral valve prolapse (20%), cysts in pancreas, lung, spleen, pineal gland, seminal vesicles; also aortic aneurysms, hepatic fibrosis, intestinal diverticula

Associated with loss of ability to concentrate urine, hypertension by age 20, infection, hematuria, renal stones (20%)

25% die from infection, 40% from hypertension and heart disease, 15% from berry aneurysms or stroke

Poor prognostic factors: sickle cell trait (not disease), men, hypertension

Xray images: angiogram

Case reports: with polycystic liver disease and hemorrhagic hereditary telangiectasia (Am J Surg Pathol 1998;22:368), 15 year old girl with no family history but classic findings and oral-facial-digital syndrome type I (Arch Pathol Lab Med 1991;115:519), with littoral cell angioma of spleen (Arch Pathol Lab Med 2001;125:1505)

Treatment: laparoscopic nephrectomy (Can J Urol 2006;13:3340), renal transplant

Clinical images: rectus abdominis diastasis and umbilical hernia; huge kidneys

Gross: large kidneys (up to 4 kg), always bilateral (although degree of involvement may vary), bosselated outer surface, composed of mass of cysts up to 4 cm; cysts contain clear to brown fluid

Gross images: enlarged kidney with variably sized cysts #1; #2; #3; #4; #5; #6; #7; with transplanted kidney; compared to normal kidney; hemorrhagic infarct with rupture

Autosomal dominant (adult) polycystic kidney disease (continued)

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Micro: cysts are saccular expansions or diverticula of all portions of renal tubule and glomerular capsule that later become disconnected and filled with fluid; cysts are lined by cuboidal or flattened epithelium, may have papillary projections or polyps; functional nephrons exist between cysts; may have foci of interstitial scarring, tubular atrophy and pyelonephritis; 20% have renal adenomas

Micro images: cysts of varying sizes #1; #2; glomerular cyst present at birth (rare)

Virtual slides: large cysts (compare to size of glomeruli

Molecular:

PKD1 gene on 16p13.3 (altered in 85-90% of cases) produces polycystin 1; function unknown (OMIM 601313)

PKD2 gene on 4q13-23 (altered in 10% of cases) produces polycystin 2; later onset and development of chronic renal failure than PKD1 (OMIM 173910)

PKD3 gene: minority of cases, gene unmapped (OMIM 600666)

10% lack a family history and are considered new mutations

References: eMedicine #1, #2, Wikipedia

Autosomal recessive (childhood) polycystic kidney disease - Kidney-tumor chapter

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Definition: autosomal recessive cystic disorder; usually bilaterally enlarged kidneys at birth

May also include older patients presenting with hepatosplenomegaly, hypersplenism, variceal bleeding and cholangitis (Medicine (Baltimore) 2006;85:1)

Epidemiology: 1 per 20,000 live births

Clinical: perinatal mortality 30-50%; 5 year survival is 80-95% if survive first month of life (Pediatrics 2003;111:1072)

Possible pulmonary hypoplasia since enlarged kidneys restrict growth of lungs; later develop portal hypertension with splenomegaly; usually no cysts other than kidney and liver

Must remove kidneys so lungs can grow; children have Potter sequence with characteristic facies due to oligohydramnios, pulmonary hypoplasia and joint deformities

Liver always affected (every portal triad, every case) with herring duct cysts, congenital hepatic fibrosis, variable bile duct ectasia and biliary dysgenesis

Clinical images: Potter facies #1; #2

Gross: markedly enlarged kidneys with smooth surface; small cysts in cortex and medulla; dilated channels are perpendicular to cortical surface; cysts are present in medulla (collecting ducts)

Gross images: markedly enlarged kidneys fill abdomen and cause pulmonary hypoplasia #1; #2; #3; kidney compared to neonate; enlarged kidneys with persistent fetal lobation #1; #2; #3; uniform distribution of small cysts; symmetrically, markedly enlarged kidney with small cysts in cortex and medulla #1; #2; dilated collecting ducts and macrocysts; renal surface shows small cysts; spongy cut surface

Autosomal recessive (childhood) polycystic kidney disease (continued)

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Micro: radially arranged cysts; dilation of all collecting tubules with fluid accumulation; cysts lined by cuboidal or flattened cells from collecting tubules

Micro images: radial arrangement of cysts with only rare glomeruli #1; #2; #3; dilated collecting ducts in cortex and medulla #1; #2; immunostains demonstrate cysts are of distal tubule/collecting duct origin #1; #2; associated congenital hepatic fibrosis

Virtual slides: dilated cysts

Molecular: mutations in PKHD1 gene (polycystic kidney and hepatic disease 1) at 6p12 (produces fibrocystin/polyductin), expressed in kidney, pancreas and liver (Braz J Med Biol Res 2006;39:1537, OMIM 263200)

References: Radiographics 2000;20:837, eMedicine, GeneReviews

Cystic renal dysplasia - Kidney-tumor chapter

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Definition: abnormal metanephric differentiation, occurring by week 20 in utero; causes persistent abnormal structures, cysts of variable size, cartilage surrounded by immature mesenchyme, lobar disorganization, no cortical-medullary demarcation

Also called multicystic renal dysplasia

Epidemiology: 90% are associated with ureteropelvic obstruction, ureteral agenesis, atresia or reflux; 10% have unknown cause; also associated with cardiac malformations, Meckel-Gruber syndrome (eMedicine), inherited metabolic abnormalities (Pediatr Nephrol 2007;22:2119), thanatophoric dysplasia type 1 (Genet Couns 2006;17:407), other familial syndromes (Am J Med Genet 1996;63:332)

Clinical: most common form of childhood cystic renal disease; causes most neonatal abdominal masses; presents as flank mass or pyelonephritis

If blastema present, patient is at risk for Wilms’ tumor

Segmental dysplasia is seen in children with duplex (duplicated) kidney (incomplete fusion of upper and lower poles)

Case reports: newborn with bilateral renal dysplasia, severe pancreatic fibrosis, intrahepatic biliary dysgenesis, total situs inversus with normal cytogenetics (Hum Path 1988;19:871)

Gross: 1/3 bilateral; large, irregular kidney, often multicystic with variably sized cysts, can’t distinguish cortex from medulla; cysts are variably sized

Gross images: multiple cysts of various sizes #1; #2; #3; #4; #5; cysts are smooth lined, no normal kidney tissue is apparent; with small bladder; due to congenital urethral stenosis with hypertrophic bladder wall and bladder diverticulum; with ipsilateral hypoplasia of ureter

Cystic renal dysplasia (continued)

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Micro: lobar disorganization; cysts of various sizes lined by flattened to cuboidal epithelium, may contain nodular blastema (undifferentiated cells), islands of undifferentiated mesenchyme, cartilage (10-20%), immature collecting ducts with fibromuscular collar, primitive glomerular structures

Micro images: large cysts lined by flattened epithelium with fibrotic and cartilaginous stroma; multiple small cysts and immature tubules, surrounded by immature connective tissue, with abortive glomerular structures; irregular cysts with occasional intervening tubules and glomeruli; immature mesenchyme and cysts #1; #2; #3; #4; islands of cartilage in stroma

Differential diagnosis:

· autosomal dominant polycystic kidney disease - familial, adults, normal kidneys at birth, alterations in PKD1, PDK2 or PKD3

· autosomal recessive polycystic kidney disease - familial, uniform cysts in neonates, cysts are radially arranged, no immature mesenchyme or cartilage, abnormalities in PKHD1 gene

· cystic nephroma - sharply demarcated from adjacent kidney by thick fibrous capsule, no renal tissue between cysts, no immature mesenchyme or cartilage

· cystic partially differentiated nephroblastoma - epithelial and stromal elements and nephroblastomatous tissue; usually hyperdiploid with trisomy 12

References: eMedicine #1, #2

Glomerulocystic kidney - Kidney-tumor chapter

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Definition: kidney with glomerular cysts; often associated with tuberous sclerosis

Also associated with maternal phenacetin use during pregnancy (Arch Pathol Lab Med 1977;101:462), hypomelanosis of Ito (Pediatr Nephrol 2008;23:1183), hemolytic-uremic syndrome (Pediatr Nephrol 2001;16:557)

Case reports: newborn with tuberous sclerosis #1 (Arch Pathol Lab Med 2000;124:327), #2 (Path Res Pract 1992;188:367), cases with tracheo-esophageal fistula and megacystic-megaureter syndrome (Diagn Pathol 2007 Apr 25;2:12), 55 year old woman (Nephrol Dial Transplant 2005;20:2293)

Gross: enlarged kidney with cortical cysts

Gross images: bilateral spongy kidneys with microcysts in cortex

Micro: dilated Bowman’s space with rudimentary or collapsed glomerular capillary tufts

Micro images: bilateral spongy kidneys with microcysts in cortex; dilated Bowman's space with rudimentary glomerular capillary tufts; bilateral cystic kidneys with megacystic-megaureter syndrome, kidney has occasional dysplastic tubules with immature mesenchymal collar (asterisk) and cystic glomeruli (arrows); glomeruli demonstrate marked dilation of Bowman's space and collapsed glomerular tufts

newborn with tubular sclerosis - figure 1: gross-sponge like kidney with numerous round, cystic spaces; fig 2: low magnification EM-cystic spaces are variably sized with glomeruli somewhere along cyst wall (small arrows) and capsule (bottom right); fig 3: EM-cells covering Bowman’s capsule are tall and columnar (large arrow); hyperplasia is also present (curved arrows); glomerulus (fat arrow) is covered by plump, irregular podocytes; fig 4: H&E shows Bowman’s capsule lining cells have eosinophilic granularity (big arrows)

Medullary sponge kidney - Kidney-tumor chapter

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Definition: bilateral, multiple cystic dilations of collecting ducts in medulla with normal cortex

Epidemiology: 1 per 5000 births; no gender preference; not familial; associated with hemihypertrophy of body (25% of cases), Marfan’s, Caroli’s, Ehlers-Danlos

Clinical: normal renal function; calcifications on Xray, stones, hematuria, infection at age 30+ years; does not progress to end stage renal disease

Treatment: cranberry juice to keep urine acid; don’t remove these kidneys

Gross: normal sized kidneys with dilated medullary ducts with multiple, small cysts in medullary pyramids and papillae, giving medulla a sponge-like appearance

Gross images: extensive cysts communicating with each other; papillae are interspersed due to variably sized cysts;

small cysts with stones, papillae on right is not affected; numerous medullary cysts and isolated cortical cyst; cysts at corticomedullary junction; cysts of inner medullary and papillary region

Micro: medullary cysts lined by cuboidal epithelium or urothelium; may have concretions adherent to cyst wall; often severe inflammation and scarring in interstitium, often with tubular atrophy near papillary tips

Micro images: cysts in papilla; with microlithiasis and chronic pyelonephritis; cortical cyst, multiple cysts at the corticomedullary junction and atypically located papillary cyst; dilated ducts and a microlith within a papillary collecting duct

References: eMedicine #1; #2

Mesothelial cysts - Kidney-tumor chapter

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Definition: rare cysts lined by mesothelial cells in vicinity of kidney

Also called primary retroperitoneal cysts of mesothelial origin

Somewhat rare

May present as renal masses

Radiologic images: figure 1A: MRI shows cystic mass (arrows) involving upper pole; fig 1B: cystic mass (arrows) at lower pole

Gross: may be hemorrhagic

Gross images: fig A/B: hemorrhagic unilocular cysts

Micro: cyst lined by single cell lining of non-pleomorphic cells with abundant eosinophilic cytoplasm, vesicular nuclei and small nucleoli; may have small gland-like spaces

Micro images: cyst lining cells have abundant eosinophilic cytoplasm, vesicular nuclei and small nucleoli; cyst lining cells are CEA-, keratin+, HBME1+, WT1+

Positive stains: keratin, vimentin, hyaluronic acid, HBME-1, WT1, thrombomodulin, calretinin

Negative stains: BerEP4, CEA, B72.3, LeuM1

Differential diagnosis:

· mucinous cystadenoma - ovarian-like stroma, mucin+, CEA+, negative for hyaluronic acid

· lymphangioma - multicystic, has smooth muscle and lymphocytes in cyst wall and lumen, keratin-

· simple hemorrhagic cyst

References: Arch Pathol Lab Med 2000;124:766

Nephronophthisis - Kidney-tumor chapter

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Definition: autosomal recessive medullary cystic kidney disease with small medullary cysts at corticomedullary junction, cortical atrophy and interstitial fibrosis

“Phthisis” means a dwindling or wasting away (Greek)

Epidemiology: 1 per million

Pathophysiology: mutations in NPHP genes (produce nephrocystins in cilia / basal body structures, Eur J Hum Genet 2009;17:406, J Am Soc Nephrol 2007;18:1855), which cause defects in signaling mechanisms that result in defects of planar cell polarity and tissue maintenance (J Am Soc Nephrol 2009;20:23)

Clinical: cortical and tubulointerstitial damage initially cause polyuria and polydipsia, progressing to chronic renal failure in 5-10 years

Consider in children/teenagers with unexplained chronic renal failure, family history, chronic tubulointerstitial nephritis on biopsy

Infantile subtype: progresses to renal failure before age 5, mutations in NPHP2 and NPHP3 genes (Kidney Int 2009 Jan 28 [Epub ahead of print]), also associated with retinitis pigmentosa, mental retardation, cerebellar ataxia, bone anomalies, liver fibrosis

Juvenile subtype: mutations in NPHP1, NPHP3-NPHP9 genes; most common cause of end stage renal disease in children and young adults, occurs at median 19 years; no gender preference; initial symptoms at age 4 years of polydipsia, polyuria, enuresis, decrease in urinary concentration, severe anemia, growth retardation; 12% associated with retinitis pigmentosa

Case reports: 4 year old girl with basal ganglia calcification and pancreatic lipomatosis (Arch Pathol Lab Med 1988;112:630)

Treatment: kidney transplant if end stage renal disease (Pediatr Transplant 2008;12:878)

Gross: bilateral involvement of normal or moderately small kidneys with contracted granular surface, thin-walled medullary cysts up to 2 cm, particularly at corticomedullary junction, which is indistinct

Gross images: cysts at corticomedullary junction, tubular cysts and interstitial infiltrate

Nephronophthisis (continued)

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Micro: cysts at corticomedullary border lined by flattened or cuboidal epithelium; also tubulointerstitial fibrosis and lymphocytic infiltrate, tubular atrophy with thickened tubular basement membrane (highlighted by PAS); glomeruli usually preserved

Micro images: tubules with thickened basal membrane; dilated collecting ducts with thickened basal membrane; dilated tubules, thickened basal membrane; deformed tubules with thickened basal membrane in fibrotic stroma; dilated tubules with lymphocytic infiltrate; tubular basement membranes thickening and cystic tubular enlargement; cysts lined by flattened epithelium and surrounded by relatively normal appearing tubules

end stage renal disease - extensive obliteration of glomeruli and sclerotic glomerli, interstitial fibrosis, atrophic tubules, chronic inflammation; preserved glomeruli with individual glomerular cysts, tubulointerstitial fibrosis, hypertrophic tubules and lymphocytic infiltrate #1; #2; #3; tubulointerstitial fibrosis, tubular cysts and lymphocytic infiltrate

EM: homogenously thickened tubular basement membrane, split into thin lamellae, reticulated or disintegrated

EM images: tubules - atrophic tubules with partly thickened, partly missing basal lamina; basal membrane shows thickening, splitting, grid like degeneration or complete absence; grid like degeneration of tubular basement membrane; thickened tubular basement membrane; partially atrophic tubule with thickened basal membrane; newly formed lamellar basal membrane; cyst wall lined with collecting duct epithelium, basal membrane is lost; collapsed glomeruli centrally, Bowman’s capsule is filled with amorphous material

glomeruli - thickened glomerular basal membrane with lacuna, periglomerular fibrosis; mild periglomerular fibrosis, thickened tubules with fragmented basal lamina, lymphocytes

References: OMIM 256100 (NPHP1)

Simple cysts - Kidney-tumor chapter

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Definition: not a disease, but an occasional finding that increases with age (0.1% in children, 20% at age 50+ years)

Clinical: 65% of renal masses, may be confused with cystic renal cell carcinoma, but avascular with smooth contours; may calcify; hemorrhage may cause acute pain

Treatment: percutaneous aspiration, continuous negative-pressure catheter drainage (AJR Am J Roentgenol 2008;190:1193), sclerotherapy

Gross: up to 10 cm, translucent with glistening membrane, filled with clear fluid, usually cortical

Gross images: simple cyst of upper pole; large cyst; multiple, smooth renal cysts filled with serous fluid; solitary, smooth kidney cyst (lower pole) filled with serous fluid; large cortical cysts with dark red blood

Micro: single layer of cuboidal, flattened or atrophic epithelium; may have thickened walls with hemosiderin-laden macrophages and atrophic epithelium

Kidney Neoplasms

Pediatric tumors

Anaplastic sarcoma - Kidney-tumor chapter

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Definition: spindle cell tumor with anaplastic changes diffusely or in multiple foci, has bizarre pleomorphic cells and atypical mitotic figures; usually chondroid differentiation

First described in 2007 (Am J Surg Pathol 2007;31:1459)

Epidemiology: mean age 12 years, median 5 years, range 1-41 years, 60% female

Case reports: 24 year old woman (ScientificWorldJournal 2009;9:97)

Clinical: often presents at advanced stage; reasonably good outcome (10/13 alive at median 8 years follow up) although may die due to metastases to lung, liver and bones

Gross: mean 13 cm, up to 21 cm; usually has cystic component, 40% involve pelvi-calyceal system

Micro: fascicular pattern of spindle cells with anaplastic changes diffusely or in multiple foci, bizarre pleomorphic cells and atypical mitotic figures; usually chondroid differentiation (benign / malignant) due to islands of hyaline cartilage or chondroid matrix, occasional foci of osteoid and primitive blastema-like areas; no epithelial structures, no nephrogenic rests

Micro images: spindle cells in collagenous stroma, also anaplastic cells in cellular focus

Positive stains: vimentin, usually desmin, often p53

Negative stains: CAM 5.2, MyoD1, CD34, CD99, WT1

Molecular: no t(x;18) of synovial sarcoma, no ETV6-NTRK3 of mesoblastic nephroma

Differential diagnosis:

· anaplastic Wilms’ tumor - prominent blastema component, foci of epithelial differentiation, occasionally nephrogenic rests, no very atypical and wildly anaplastic cells in stroma and cartilage; blastema areas are WT1+ and CD56+

· sarcomatoid carcinoma - has keratin+ epithelial component

Clear cell sarcoma - Kidney-tumor chapter

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Definition: monotonous proliferation of uniform small round cells with evenly distributed fine chromatin, separately by uniform vascular network

Also called bone metastasizing renal tumor

Epidemiology: mean age 36 months, range 2 months-14 years, peaks at ages 2-3 years; 2/3 male, graph

4% of childhood renal tumors; 20 new cases per year in US; rarely in teenagers / adults (Am J Surg Pathol 1999;23:1455)

Clinical: frequent relapse; bone and skull metastases common; also metastases to regional lymph nodes (29% at presentation), brain, lung, liver; metastases often 5 years or more after removal of primary tumor

Overall survival 69%, 98% for stage 1

Favorable prognostic factors: treatment with doxorubicin and low stage; death more common after combination chemotherapy other than doxorubicin

Case reports: congenital tumor with metastases (Virchows Arch 2005;446:566), 19 year old man with renal mass (UPMC #201)

Gross: large (mean 11 cm), well circumscribed, centered in central kidney or medulla; homogenous tan/gray or myxoid appearance; firm with occasional cysts

Gross images: large tan-yellow mass; well-circumscribed, bulging white tumor; fleshy yellow-tan tumor (fig 1A)

Micro: nests or cords of small cells with indistinct cell margins; light staining cytoplasm, round nuclei containing fine chromatin and grooves, no nucleoli, rare mitoses; only 20% have clear cells (due to vacuoles); vascularized stroma separating nests is alveolar and arborizing, scattered preexisting tubules or glomeruli are trapped in periphery of tumor; vascular invasion common; other patterns are myxoid (50%), sclerosing (35%, includes hyalinizing which has osteoid-like pattern resembling osteosarcoma), cellular (26%), epithelioid (13%, tumor cells align along vessels), palisading (11%), spindle (7%), storiform (4%) and anaplastic (3%)

Clear cell sarcoma (continued)

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Micro images: classic pattern - tumor-kidney junction showing entrapment of individual nephrons by tumor cells extending into the adjacent renal parenchyma; evenly distributed vascular network; sheets of monotonous cells with indistinct cell margins, pale cytoplasm, round/oval nuclei with fine chromatin #1; #2; hypocellular spindle cell appearance; various images #1; #2; cell cords demarcated by delicate fibrovascular arcades #1; #2; numerous cytoplasmic vesicles; in this field, the tumor cytoplasm is more compact and less vesicular, and the nuclei are pale and frequently empty; cord cells are spindled, but vascular septa are still recognizable; proliferation of septal cells imparts a prominent spindled pattern; EGFR+

other findings - rosettes; pleomorphic tumor giant cells; hyalinizing pattern; epithelioid pattern; filigree pattern; myxoid and cystic pattern; palisading pattern reminiscent of schwannoma; pericytomatous pattern; sclerosing pattern; trabecular pattern

comparison with nephroblastoma - nephroblastoma (left) and clear cell sarcoma (right)-note the more uniform appearance and paler blue color of clear cell sarcoma; entrapped single renal tubules with cystic dilatation of one tubule, resembles nephroblastoma; cord cells have become condensed, creating cohesive epithelioid ribbons that can be confused with nephroblastoma

Cytology: moderate pale blue cytoplasm (Cytopathology 2008;19:80), cord cells with few stromal fragments; spindle cell variant has myxoid stromal fragments and septal cells, anaplastic variant has bizarre pleomorphic nuclei, coarse chromatin and atypical mitotic figures (Diagn Cytopathol 2005;33:83)

Cytology images: irregular nuclear borders, coarse chromatin and nuclear folding / grooves

Clear cell sarcoma (continued)

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Positive stains: vimentin

Negative stains: keratin, EMA, S100, CD99, WT1, p53, desmin

EM: rare organelles, sparse cytoplasmic filaments, primitive cell junctions, complex cytoplasmic processes

Molecular: t(10;17)(q22;p13), t(10;17)(q11;p12), interstitial deletions of #14q (Arch Pathol Lab Med 2007;131:446)

Molecular images: t(10;17)(q22;p13) and interstitial deletion of 14q

DD: Wilms’ tumor - pushing border, more aggressively invasive, cells are less uniform and more hyperchromatic, epithelioid areas are keratin+

References: Am J Surg Pathol 2000;24:4, Hum Path 1985;16:1219, eMedicine

Mesoblastic nephroma - Kidney-tumor chapter

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Definition: congenital tumor resembling infantile fibromatosis or leiomyoma, with fascicles and whorls of bland myofibroblasts and thin collagen fibers; cellular variant resembles infantile fibrosarcoma

Also called fetal, mesenchymal or leiomyomatous hamartoma

First described in 1967 (Pediatrics 1967;40:272)

Epidemiology: most common renal tumor of infancy, 5% of pediatric renal tumors (Cancer 2006;106:2275); age at presentation varies by type (classic: 16 days, cellular: 5 months, mixed: 2 months); may present in utero causing nonimmune fetal hydrops and polyhydramnios

Unlikely to occur in patients over 2 years old

Age distribution curve

Frequency: classic (24%), cellular (66%), mixed (10%)

Clinical: excellent prognosis (5 year survival of 96%, Pediatr Blood Cancer 2008;50:1130), 5-10% recur or metastasize (usually cellular type), usually by age 1 year, to lung, brain or rarely bone

Cellular variant in perinatal period may have poor prognosis (Pediatr Surg Int 2007;23:205)

Features to report: whether tumor involves medial kidney margin

Case reports: classic type in newborn (Arch Pathol Lab Med 2002;126:103), 3 week old infant with flank mass and mixed type (Arch Pathol Lab Med 2004;128:929), 2 month old with cellular variant conceived by in vitro fertilization (J Pediatr Surg 2008;43:E27), 3 month old girl with cellular type (Case of Week #57)

Treatment: nephrectomy with wide margins; chemotherapy if resection is incomplete in infants 3 months or older or if tumor ruptures during surgery

Gross: classic - mean 5 cm, variably circumscribed, white/yellow whorled mass near hilum, involving over half of kidney with indistinct tumor-kidney interface; resembles leiomyoma with whorled cut surface; may be cystic; may involve renal sinus; hemorrhage and necrosis uncommon

cellular - mean 9 cm, necrosis, large cystic areas and hemorrhage

mixed - mean 10 cm; cysts, hemorrhage and necrosis in cellular areas

Gross images: image; tan fleshy mass with hemorrhage, necrosis and cystic degeneration; rubbery, solid, homogenous tumor invades the renal parenchyma; well circumscribed with white fibrous cut surface

Mesoblastic nephroma (continued)

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Micro: classic, cellular and mixed types

Classic - resembles infantile fibromatosis or leiomyoma with fascicles and whorls of bland spindled myofibroblasts and thin collagen fibers; tumor surrounds tubules and glomeruli, has irregular borders; metaplastic and dysplastic elements common, usually cartilage, also extramedullary hematopoiesis and cuboidal metaplasia; usually few mitotic figures; no desmoplasia

Cellular - also called atypical, resembles infantile fibrosarcoma with densely packed plump atypical spindle cells with abundant cytoplasm, vesicular nuclei and nucleoli; frequent mitotic figures (25-30/10 HPF) and necrosis

Micro images: classic pattern - monotonous spindle cells with abundant cytoplasm and bland nuclei #1; #2, cellular areas have mitotic figures, cystic degeneration, hemorrhage and necrosis; prominent interlacing bundles; resembles fibromatosis; tumor interdigitates with renal parenchyma #1; #2; #3; #4; perirenal invasion with characteristic angiomatous vascular proliferation at advancing edge; extension into renal sinus and along structures medial to the kidney is an important feature of most lesions; embryonal metaplasia of Bowman capsule and entrapped tubules #1; #2, accompanied by epithelial hyperplasia; mitotic figures

cellular pattern - plump spindle cells growing in a diffuse pattern; cellular and classic appearance; cellular variant has monomorphous sheets of closely packed spindle cells imparting a small blue cell appearance, and prominent irregular vascular spaces; dense spindle cells with mitotic activity

mixed type - image

Case of Week #57 - well circumscribed; medium power; high power; infiltrative margin; glomerular entrapment; angiomatoid area

resembling other tumors - left-mesoblastic nephroma; right-consistent with infantile fibrosarcoma #1; #2; fig A: classic mesonephric nephroma features, fig B: resembles clear cell sarcoma; fig A: typical of cellular mesoblastic nephroma; B: invasive edge shows more hyperchromatic, epithelioid-appearing cells with prominent nucleoli; C: resembles rhabdoid tumor but t(12;15) fusion product was present

Mesoblastic nephroma (continued)

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Virtual slides: mesoblastic nephroma

Cytology: cellular variant - cellular clusters of spindle cells, mild nuclear pleomorphism, mitotic activity, no blastema (Diagn Cytopathol. 2009 Feb 13 [Epub ahead of print])

Positive stains: smooth muscle actin, desmin, vimentin; also renin (within tumor vessels or vessels in trapped cortex, Hum Path 1988;19:1347); occasionally WT1 (J Pediatr Hematol Oncol 2008;30:768)

Negative stains: keratin (except for entrapped epithelium), laminin

Molecular: cellular subtype has t(12;15)(p13;q25) translocation, results in ETV6-NTRK3 fusion gene, also present in infantile fibrosarcoma (Mod Path 2000;13:29, Mod Path 2001;14:1246); mixed and classic subtypes lack this translocation (Histopathology 2006;48:748); cellular and mixed variants also have trisomy 11, duplication of paternal IGF2 allele and increased expression of IGF2 mRNA (Genes Chromosomes Cancer 2007;46:929)

Molecular images: ideogram and FISH; gel for fusion transcript

Differential diagnosis:

· adult mixed epithelial and stromal tumor - mean age in 50’s, usually women, similar morphology and staining pattern, also positive for estrogen and progesterone receptors

· clear cell sarcoma - similar age but has clear cells and chicken-wire vasculature, tumor cells isolate single nephrons, fine nuclear chromatin and low mitotic rate; negative for smooth muscle markers

· metanephric stromal tumor - older age, nodular low power pattern, onion-skin cuffing around entrapped renal tubules, heterologous differentiation and vascular changes, CD34+

· rhabdoid tumor - more invasive margins, usually epithelioid cells with cytoplasmic inclusions and prominent nucleoli, usually presents with metastases

· Wilms’ tumor - older age, also has blastema and nephrogenic rests; previously treated tumors may have well differentiated spindle cell stroma

References: Hum Path 1989;20:682, eMedicine

Metanephric stromal tumor - Kidney-tumor chapter

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Definition: benign abdominal mass in infants (mean age 2 years), centered on renal medulla, with bland spindle cells that entrap native kidney

Often misdiagnosed as mesoblastic nephroma

May be related to Wilms’ tumor (Clin Lab Med 2005;25:379)

Treatment: excision is curative

Gross: fibrous lesion centered in renal medulla containing smooth walled cysts; mean 5.5 cm

Micro: nodular low power appearance; identical to stromal component of metanephric adenofibroma; unencapsulated bland spindle cells that entrap native kidney, usually undermine calyceal or pelvic urothelium, may entrap nerves, often has scalloped border with renal cortex; hypo- and hypercellular areas with onion-skin cuffing around entrapped renal tubules; spindle cells have thin, tapered, hyperchromatic nuclei with thin or indistinct cytoplasmic extensions; occasional epithelioid cellular stroma; stroma may show glial, cartilaginous or neuroblastic differentiation, angiodysplasia of entrapped arterioles and juxtaglomerular cell hyperplasia in entrapped glomeruli; no vascular invasion, no mitotic figures

Micro images: hypo- and hypercellular areas

Virtual slides: metanephric stromal tumor

Positive stains: vimentin, CD34 (often patchy), S100 (variable)

Negative stains: smooth muscle actin, muscle specific actin, desmin, keratin and EMA (but entrapped tubules are positive), CD117/c-kit, low Ki-67 index

Differential diagnosis:

· clear cell sarcoma - regular branching capillary vascular pattern, no heterologous differentiation, CD34-

· mesoblastic nephroma - classic variant has whorls and fascicles, metaplastic and dysplastic elements common, actin+, desmin+, CD34-

· metanephric adenofibroma - neoplastic epithelium, not entrapped tubules

References: Am J Surg Pathol 2000;24:917

Nephroblastomatosis / nephrogenic rests - Kidney-tumor chapter

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Definition: massive aggregates of primitive metaplastic tissue that persists after nephrogenesis ends

Epidemiology: 1% of neonatal kidneys

Clinical: florid cases associated with congenital anomalies and hypertension

Precursor lesion of Wilms’ tumor, found in 30-44% of kidneys resected for Wilms’ tumor

Intralobar rests: progress to Wilms’ tumor at higher rate than perilobar rests, more commonly associated with WT1 mutations, Denys-Drash syndrome and WAGR syndrome

Perilobar rests: may progress to malignancy, associated with genetic/epigenetic dysregulation at 11p15 (Clin Cancer Res 2008;14:7635); associated with idiopathic hemihypertrophy and Beckwith-Wiedemann syndrome

Case reports: male newborn death with bilateral nephroblastomatosis (Arch Pathol Lab Med 1989;113:729), siblings with universal nephroblastomatosis with nephromegaly (Pediatr Dev Pathol 2009;12:47), lumbosacral ectopic rest in newborn (Am J Surg Pathol 2004;28:1389)

Treatment: conservative

Gross: single or multiple, unilateral or bilateral; diffuse involvement of entire subcapsular region

Gross images: perilobar nephrogenic nests #1; #2

Micro: tightly packed nephrogenic cells with primitive appearance, but not anaplastic; perilobar or intralobar; scanty stroma; no cartilage or primitive mesenchyme microscopic aggregates

Intralobar: randomly distributed throughout cortex and medulla with irregular margins, more stroma than blastema or tubules

Perilobar: peripheral with sharply demarcated margins, composed of blastema and tubules with scanty or sclerotic stroma, often solitary

Micro images:

intralobar - small interstitial lesion mixed with normal nephronic elements #1; #2; mature and immature elements throughout renal parenchyma; sclerosing intralobar nephrogenic rest with mature spindle cell stroma and a few residual blastemal islands, may resemble focal renal dysplasia; neoplastic intralobar rest; mature and immature elements are intermingled throughout the renal parenchyma

perilobar - microscopic rests composed of blastemal cells, are termed "incipient" in neonates and "dormant" otherwise #1; #2; #3; sclerosing perilobar nephrogenic rest; focal scarring; hyperplastic perilobar rest in sclerosing stage; multifocal hyperplastic perilobar rests; nearly confluent rind of perilobar rest tissue; thick rind of perilobar tissue; neoplastic perilobar rest #1; #2

DD: Wilms’ tumor (neoplasm)

References: Adv Anat Path 2001;8:276

Neuroblastoma - Kidney-tumor chapter

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Definition: small blue cell tumor with Homer-Wright rosettes; either primary renal tumor, secondary spread from adrenal or other retroperitoneal site or metastasis

See also adrenal gland chapter

Clinical: metastasizes to bone and orbit

Poor prognosis: N-myc amplification (30%) or 1p-

Laboratory: catecholamines in serum and urine

Case reports: kidney invasion through capsule (J Pediatr Surg 1994;29:930), primary kidney tumor in adults (J Urol 1987;137:966)

Gross images: adrenal tumor encasing kidney

Micro: small blue cell tumor with Homer-Wright rosettes

Positive stains: catecholamines (90%), NSE, S100

Differential diagnosis: Wilms’ tumor - has blastema, epithelioid structures and fibroblast-like stroma

Oncocytoid renal cell carcinoma after neuroblastoma - Kidney-tumor chapter

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Only one published article regarding neuroblastoma (Am J Surg Pathol 1999;23:772), but similar tumor described after treatment for cardiac leiomyosarcoma (Urology 2007;70:e13)

Clinical: 4 cases described with mean age 9 years, range 5-13 years; mean interval between neuroblastoma and carcinoma of 7 years (range 3-12 years)

Micro: expansile masses composed of solid and papillary patterns of large cells with well defined cell membranes, abundant eosinophilic, oncocytic or reticular cytoplasm; enlarged nuclei with mildly irregular contours, distinct nucleoli; occasional lipid-laden histiocytes, psammoma bodies, mitotic figures; may resemble high grade papillary renal cell carcinoma, but predominantly solid and without necrosis

Positive stains: EMA, vimentin; variable CK 20

Negative stains: HMB45, S100, CK7

Molecular: loss of 20q13; also other changes not typical for renal cell carcinoma

EM: microvilli and cell junctions, less mitochondria than oncocytoma; no microvesicles

Ossifying renal tumor of infancy - Kidney-tumor chapter

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Definition: rare calcified mass in renal pelvis composed of spindle cells in partially calcified osteoid matrix

Clinical: presents as gross hematuria or abdominal mass; benign behavior

Case reports: 8 week and 2 year old children (J Pediatr Urol 2007;3:258)

Micro: spindle cells with focal osteoid matrix

Micro images: spindle cells with focal osteoid matrix; osteoid core

References: Pediatr Pathol Lab Med 1995;15:745

Renal cell carcinoma in children - Kidney-tumor chapter

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Epidemiology: 1/3 associated with either tuberous sclerosis, neuroblastoma, teratoma with chemotherapy, Saethre-Chotzen syndrome, chronic renal failure or related diseases in family members (Cancer 2006;107:2906)

Clinical: 4% of renal tumors in children (Pediatr Blood Cancer 2009;52:237)

Subtypes: 22% papillary, 20-46% translocation (Am J Clin Pathol 2006;126:349, Histopathology 2008;53:533), 15% clear cell, 8% Wilms’ associated, 5% collecting duct, 5% chromophobe, 24% unclassified (Am J Surg Pathol 2004;28:1117)

Case reports: 3 year old girl (Saudi J Kidney Dis Transpl 2009;20:124)

Treatment: excision (Pediatr Surg Int 2007;23:327), retroperitoneal lymph node dissection recommended (Pediatr Blood Cancer 2008;51:475)

References: Am J Surg Pathol 1999;23:795

Rhabdoid tumor - Kidney-tumor chapter

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1-2% of childhood renal tumors

Epidemiology: 60% are <1 year old, 30% 1-3 years old, rare > 5 years, age distribution

15% are associated with primary embryonal tumors in the midline posterior fossa, often medulloblastoma

Clinical: usually stage 2 or higher; 9% are bilateral

Very aggressive; 82% present with metastases; 90% die in 2 years

Case reports: two male neonates with presentation as skin metastasis (Arch Pathol Lab Med 1998;122:1099), 10 year old girl with pelvic tumor (Arch Pathol Lab Med 2003;127:633), 38 year old woman (Arch Pathol Lab Med 2003;127:e371)

Treatment: high dose chemotherapy, possibly autologous hematopoietic stem cell transplant (Pediatr Blood Cancer 2009 Mar 3 [Epub ahead of print])

Gross: solid, soft, well circumscribed, involves medullary region

Gross images: soft tan tumor; round lobulated mass

Micro: diffuse, trabecular or alveolar pattern of large monomorphic cells with well defined cell borders; cells have pink cytoplasm; cleared chromatin, macronucleoli and eccentric nuclei due to large eosinophilic hyaline globule (perinuclear inclusions); tumor has aggressive invasive pattern; occasionally cells are spindled; variable necrosis and mitoses

Micro images: high grade tumor with abundant cytoplasm, perinuclear inclusions and prominent nucleoli #1; #2; #3; #4; #5; aggressive infiltration of vessels in renal parenchyma and sinus is characteristic; sheets of tumor cells surround glomerulus; rhabdoid and medullary tumors, H&E and INI1

patterns: epithelioid, possibly from replacement of preexistent tubular structures in renal medulla; hyalinizing; chondroid

case reports: 10 year old girl - Fig 1: CT shows large calcified mass in pelvic brim, fig 2/3: nodules of large, cells with well defined cell borders, abundant eosinophilic cytoplasm pushing nuclei to periphery, karyotype shows +X, +2 +7 plus other changes

38 year old woman - various images

Rhabdoid tumor (continued)

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Positive stains: keratin (particularly CK8), vimentin, EMA

Negative stains: muscle markers, neural markers, WT1, HSNF5/INI1 (nuclear stain, Am J Surg Pathol 2004;28:1485, Mod Pathol 2006;19:717)

EM: hyaline globules composed of tangled intermediate filaments

Molecular: deletions or mutations of hSNF5/INI1/SMARCB1 gene at 22q11.2 (use FISH) (OMIM 601607), which is associated with loss of INI1 nuclear staining (Pathology 2008;40:664); also seen in renal medullary carcinoma (Mod Pathol 2008;21:647) and epithelioid sarcoma (Am J Surg Pathol 2008 Nov 19 [Epub ahead of print])

DD: tumors that may have rhabdoid features focally, but are IN1+ include: collecting duct carcinoma, Ewing’s/PNET, mesoblastic nephroma, renal cell carcinoma, urothelial carcinoma, Wilms’ tumor

References: Am J Surg Pathol 1989;13:439, eMedicine

Translocation carcinoma (children) - Kidney-tumor chapter

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Definition: tumor has gene fusion involving TFE3 transcription factor gene

Also called MiT translocation subgroup carcinomas

Represents 33-73% of pediatric renal cell carcinomas (Cancer 2008;112:1607)

Associated with prior chemotherapy (J Clin Oncol 2006;24:1529)

Clinical: presents at high stage with poor prognosis (Histopathology 2008;53:533)

Gross: tan-yellow, frequent hemorrhage and necrosis

Gross images: multiple partially cystic and hemorrhagic tumor nodules with fibrous septa

Micro: fibrous pseudocapsule, often calcified; papillary and nested growth pattern with clear cells; polygonal tumor cells with sharp cell borders, voluminous clear to eosinophilic cytoplasm, irregular nuclei containing vesicular chromatin and small nucleoli; surrounded by thin walled vessels; frequent calcifications; also minor solid, acinar, alveolar and tubular patterns; no/rare mitotic figures

Note: cases with TFE translocations rarely have melanin pigment and morphologically resemble PEComas (Am J Surg Pathol 2009;33:609)

Micro images: various images #1; #2; t(6;11) tumors

Virtual slides: #1; #2

Positive stains: RCC, TFE3 (nuclear staining) or TFEB (nuclear staining), CD10, AMACR, vimentin; also E-cadherin (2/3), cytokeratin (30-50%), EMA (50%, frequently only focal); weak expression of melanocytic markers (Am J Surg Pathol 2002;26:1553, Am J Surg Pathol 2008;32:656); also p21, cyclin D1 (Pathol Res Pract 2009 Feb 24 [Epub ahead of print])

Negative stains: CD45, HMB45, calretinin, smooth muscle actin, p53

Molecular: t(X;17)(p11.2;q25) - balanced translocation of TFE3 gene at Xp11.2 and ASPL gene at 17q25; also found in alveolar soft part sarcoma, but unbalanced

t(X;1)(p11.2;q21) - TFE3 and PRCC genes

t(6;11)(p21;q12) - TFEB and alpha genes; appear to have low malignant potential, in contrast to other translocation carcinomas (Am J Surg Pathol 2005;29:230)

Hereditary papillary carcinoma: t(X;1)(p11.2; p34) - fusion of TFE3 and PSF

Molecular images: ideogram and karyotype

Translocation carcinoma (children) (continued)

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EM: features of clear cell carcinoma, including cell junctions, numerous mitochondria, microvilli, basement membrane, abundant glycogen

Differential diagnosis:

· clear cell renal cell carcinoma - usually older patients, no papillary pattern, vimentin+, keratin+, TFE3-, 3p-, no intracisternal microtubules on EM

· papillary renal cell carcinoma - predominantly papillary, no nested alveolar patterns, no extensive areas of clear cells, keratin+, TFE3-, trisomy 7 and 17

· clear cell sarcoma of kidney - TFE3 negative

Wilms’ tumor of children - Kidney-tumor chapter

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Definition: triphasic tumor, usually children, with undifferentiated blastema, fibroblast-like stroma and epithelium

Also called nephroblastoma

First described by German surgeon Dr. Max Wilms (reference)

Epidemiology: most common kidney tumor of childhood, affecting 1 per 8-10,000 children; 500 new cases/year in US

No gender preference; 90% occur before age 6 years, only rarely congenital; occasionally in teenagers or adults; age distribution

Associated with WAGR, Denys-Drash and Beckwith-Wiedemann syndromes (although most are sporadic) and nephroblastomatosis

WAGR syndrome: Wilms’ tumor (1/3), Aniridia, Genitourinary anomalies, mental Retardation; due to 11p13 deletion (WT1); also intralobar nephrogenic rests (OMIM 194072)

Denys-Drash syndrome: gonadal dysgenesis (male pseudohermaphroditism), glomerulosclerosis and Wilms’ tumor; also intralobar nephrogenic rests; most develop Wilms’; have WT1 dominant negative missense mutation, NOT a deletion (Am J Surg Pathol 1983;7:387, Hum Path 1987;18:80, eMedicine)

Beckwith-Wiedemann syndrome: exophthalmos, macroglossia and gigantism; also hemihypertrophy, renal medullary cysts, adrenal cytomegaly, hypoglycemia; have 11p15.5 abnormality, may be due to genomic imprinting; higher risk for hepatoblastoma, adrenocortical tumors, rhabdomyosarcoma, pancreatic tumors, perilobar nephrogenic rests (OMIM 130650, eMedicine)

Clinical: presents as large abdominal mass felt by mother holding child; occasionally extrarenal (retroperitoneum, sacrococcygeal region, testis, uterus, inguinal canal, mediastinum); may present with lung metastases or traumatic rupture

Spreads into perirenal soft tissue; may invade renal vein; metastasizes to regional lymph nodes (15%), lung, liver, peritoneum; rarely bone (1%)

Tissue diagnosis important as clinical diagnosis is wrong in 5%; FNA and frozen section are unreliable

Origin: apparently derives from nephrogenic blastema cells

Wilms’ tumor of children (continued)

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Staging (National Wilms Tumor Study Group)

Stage I (43%): tumor limited to kidney and completely resected, renal capsule intact, tumor not ruptured or biopsied prior to removal, no residual tumor beyond margins of resection, no tumor within renal vein (tumor within intrarenal vessels is OK), no nodal involvement or distant metastases

Stage II (23%): tumor extends beyond kidney but is completely resected, regional extension of tumor (vascular invasion outside of renal parenchyma or within the renal sinus, or capsular penetration but with negative surgical margin), operative tumor spill confined to flank (no peritoneal contamination), tumor biopsy (except FNA) prior to surgery

Stage III (23%): nonhematogenous metastases to abdomen only (such as regional lymph nodes), including tumor implants in or penetrating peritoneum; gross or microscopic tumor present postoperatively (i.e. positive resection margins), tumor spill before or during surgery not confined to flank, removal of tumor in > 1 piece

Stage IV (10%): hematogenous metastases or nodal metastases outside of abdominopelvic region (e.g. lung, liver or elsewhere beyond renal drainage system)

Stage V (5%) bilateral renal involvement at diagnosis (but each side should be staged separately as I-IV above)

References: Pediatr Dev Pathol 2005;8:320

Poor prognostic factors for Wilms’ tumor:

(a) anaplasia in stage II-IV tumors; diffuse anaplasia is worse than focal anaplasia but even small foci are associated with poor prognosis due to chemotherapy resistance

(b) high stage (most epithelial-predominant tumors are stage I; most blastema-predominant tumors are stage III/IV)

(d) large size

Wilms’ tumor of children (continued)

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Teratoid Wilms’ tumor: rare; Wilms’ tumor that arises within a teratoma; has large variety of tissues resembling teratoma; usually presents at high stage and has high mortality (J Pediatr Urol 2007;3:282)

Case reports: infant that also has neuroblastoma and Fanconi’s anemia (Hum Path 2002;33:1047), 7 year old boy with teratoid tumor (Arch Pathol Lab Med 1998;122:925), 7 year old girl with sudden death due to tumor emboli (Arch Pathol Lab Med 1990;114:605), immature glomeruli and aberrant glomerulogenesis (Arch Pathol Lab Med 1988;112:536), botyroid tumor of renal pelvis (Arch Pathol Lab Med 1984;108:147), with membranoproliferative glomerulonephritis, focal and segmental glomerulosclerosis (Arch Pathol Lab Med 1984;108:141), with hemihypertrophy and bilateral, sequential tumors (Arch Pathol Lab Med 1978;102:639), extrarenal tumors thought due to displaced mesonephric / metanephric rests (Hum Path 1989;20:691), bilateral cystic nephroblastomas and multiple malformations (Hum Path 1985;16:754)

Treatment of Wilms’ tumor:

80-90% overall are cured; a small percentage develop second neoplasms

Treatment information from US National Cancer Institute

Gross: large, solitary, well-circumscribed mass (10% bilateral or multicentric), soft, homogenous, tan-gray; hemorrhage, necrosis, cysts and lobular pattern are common

Grossing notes: take sections through the renal pelvis/sinus and include medial sinus margin (medial end of soft tissues surrounding renal artery and vein), junction between normal kidney and tumor, tumor capsule and uninvolved kidney; document where sections are taken on a diagram, snap freeze tumor and normal tissue for molecular studies (Arch Pathol Lab Med 2003;127:1280)

Gross images: well circumscribed tumor with hemorrhage and necrosis #1; #2; necrotic kidney tumor and adherent ileum; gray spherical tumor; tumor protrudes into the renal pelvis resembling botyroid rhabdomyosarcoma; metastases to lung

Wilms’ tumor of children (continued)

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Micro: triphasic with undifferentiated blastema (cellular with small blue primitive cells with scanty cytoplasm, nuclei are overlapping with finely dispersed chromatin; patterns are diffuse, nodular, cordlike or basaloid), fibroblast-like stroma and epithelium (abortive tubules, glomeruli with elongate/ovoid nuclei having molded/wedged shapes); may have smooth muscle, cartilage, adipose tissue, squamous or mucinous epithelium, bone, neural tissue; prominent skeletal muscle is associated with bilateral tumors in young children

Severe nuclear unrest: nuclear pleomorphism or atypia approaching, but insufficient for anaplasia

Anaplasia: 5% of cases; hyperchromatic, pleomorphic nuclei are 3x larger than adjacent cells, plus abnormal mitotic figures

Focal anaplasia: all conditions must be met - (a) no anaplasia in tumor within renal vessels or outside kidney; (b) random biopsies are free of anaplasia; (c) anaplasia confined to sharply localized regions within primary intrarenal tumor site and (d) each focus of anaplasia must be surrounded on all sides by nonanaplastic tissue which does not show severe nuclear unrest (Am J Surg Pathol 1996;20:909)

Diffuse anaplasia: any conditions met - (a) anaplasia in tumor in any extrarenal site, including vessels of renal sinus, extracapsular infiltrates, metastases or intrarenal vessels; (b) anaplasia in random biopsy; or (c) anaplasia unequivocally present in 1 region of tumor, with extreme nuclear unrest elsewhere in the lesion

Renal sinus vascular invasion: tumor fills lumen or invades vessel wall; also free floating rounded tumor fragments not associated with other displacement artifact

Note: epithelial cell complexes from damaged nephrons, metaplastic calyceal urothelium, mesothelial inclusions and Tamm-Horsfall protein within nodal sinuses may be mistaken for metastases (Hum Path 1990;21:1239)

Micro images: diagram of renal sinus and tumor invasion; tumor within vessels and soft tissue of the renal sinus; tumor compresses renal medulla; triphasic tumor #1; #2; #3; #4; expansive triphasic tumor in normal kidney; blastema, primitive glomeruli and tubules; blastema with glomeruloid epithelial structure; mature pattern with glomerular, tubular, and stromal cells showing little or no proliferative activity; blastema, epithelium and mitotic figures; blastema with cribriform epithelial component

blastema - #1; #2; invasive diffuse blastemal pattern #1; #2-resembles other small cell tumors of childhood; #3 with cohesive cells showing evidence of early tubulogenesis; serpentine pattern; serpentine and diffuse patterns; nodular pattern; basaloid pattern

Wilms’ tumor of children (continued)

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Micro images:

epithelium - monophasic epithelial pattern is predominant; embryonal tubular pattern, with tall columnar cells and small lumina; tubular structures predominate in this lesion; mature tubulopapillary pattern with low cell density and no/rare mitotic figures; tubular and glomerular differentiation; relatively mature glomeruli; tubules and rosettes; rosettes in PNET (for comparison) often lack the nuclear concentration around the center of the rosette; rosettes in neuroblastoma have nuclear concentration around the center of the rosette; mucinous epithelium may be prominent; squamous epithelial focus

teratoid nephroblastoma - ciliated epithelium; cluster of 6 mature ganglion cells is present centrally with other mature tubular and stromal elements; neuroglial differentiation was confirmed by GFAP staining

other features - skeletal muscle is common tumor element #1; #2; botyroid protrusions of tumor cells into lumen of the pelvicaliceal system; adipose differentiation with associated nodule of skeletal muscle; cartilage formation; heterologous stromal elements (striated muscle)

anaplasia - anaplasia; huge, irregular-shaped nuclei are a major criterion for recognition of anaplasia; sharply demarcated nodular region (left side) was only site of anaplasia; multipolar mitotic figure; true tripolar mitosis (left edge) has each limb nearly the size of a normal metaphase plate (right lower corner); X-shaped mitotic figure (left upper corner) is similar size as metaphase plate in right lower corner, may be due to uneven separation of a normal metaphase, and is NOT a multipolar mitotic figure

post-chemotherapy - total tumor necrosis; persistence of mature skeletal muscle

stains - H&E and INI1+

Wilms’ tumor of children (continued)

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Virtual slides: #1; #2; #3-mixed subtype

Videos: #1

Positive stains: blastema - WT1, desmin but not other muscle markers (Mod Path 1997;10:895), focal vimentin

epithelium - WT1, keratin, EMA; tubules are CK57+

stroma - weak WT1; other stains consistent with morphologic appearance (myogenin if rhabdomyoblastomatous, S100 if neural, etc.)

Negative stains: blastema negative for CK7, CD57, usually p53; epithelium negative for vimentin

Molecular: abnormal expression of WT1 (11p13, encodes zinc finger transcription factor expressed early in urogenital system development) and WT2 (11p15.5); p53 abnormalities in anaplastic foci; no t(12;15) of cellular mesoblastic nephroma; no t(11;22) of Ewing’s/PNET; no 22q11.2 abnormalities of rhabdoid tumor; no N-myc of neuroblastoma

EM: resembles developing metanephros with well developed cell junctions, microvilli, layer of thick flocculent coating around cell surface

Differential diagnosis:

· neuroblastoma - no triphasic patterns; has rosettes with no lumen, >1 cell layer, no distinct basal lamina, in contrast to Wilms’ immature tubules which have a lumen, a single cell layer, distinct basal lamina and surrounding fibromyxoid stroma

· perilobar nephrogenic rest - no fibrous capsule

· renal cell carcinoma may resemble epithelial predominant Wilms’

· small blue cell tumors - if blastema predominates

References: Wikipedia, eMedicine

Cystic partially differentiated nephroblastoma

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WHO definition: rare multilocular cystic neoplasm of very young children, has epithelial and stromal elements and nephroblastomatous tissue

Usually hyperdiploid with trisomy 12

Case reports: hyperdiploidy and trisomy 12 (Hum Path 1996;27:980)

Gross images: numerous thin walled cysts

Micro images: embryonal elements are present, but conform to the septa between cysts; cysts with hobnail epithelium

DD: cystic nephroma

Benign (usually) adult tumors

Classification of renal cell carcinoma - Kidney-tumor chapter

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Based on cytology, tissue characteristics (Thoenes, Storkel & Rumpelt, Path Res Pract 1986;181:125) and cytogenetics

Heidelberg classification: J Path 1997;183:131

Recommended to not use granular cell variant of renal cell carcinoma (Urology 2007;69:452)

Recommended to not use sarcomatoid carcinoma, but to classify as high grade carcinoma of type from which it originated, or as unclassified (Cancer 1997;80:987)

WHO (2004) Classification

Kidney Tumors in Infants and Children:

Nephroblastic Tumors

Nephroblastoma

Favorable histology

Anaplasia (diffuse and focal)

Nephrogenic rests and nephroblastomatosis

Cystic nephroma and cystic partially differentiated nephroblastoma

Metanephric tumors and related entities

Metanephric adenoma

Metanephric adenofibroma

Metanephric stromal tumor

Mesoblastic Nephroma

Cellular

Classic

Mixed

Clear Cell Carcinoma

Rhabdoid Tumor

Renal Epithelial Tumors of Childhood

Papillary renal cell carcinoma

Renal medullary carcinoma

Renal tumors associated with Xp11.2 translocations

Rare tumors

Ossifying renal tumor of infancy

Angiomyolipoma

Renal Tumors and Tumor-Like Conditions of Adults:

Renal Cell Carcinoma

Renal Cortical Adenoma

Metanephric Tumors

Metanephric adenoma

Metanephric adenofibroma

Metanephric stromal tumor

Metanephric adenosarcoma

Oncocytoma

Rare Tumors with Epithelial and/or Parenchymal Differentiation

Carcinoid Tumor

Small cell carcinoma

Primitive neuroectodermal tumor

Juxtaglomerular cell tumor

Teratoma

Nephroblastoma and other “pediatric” renal tumors

Multilocular cyst (cystic nephroma)

Mixed epithelial and stromal tumor

Spiradenocylindroma

Mesenchymal Tumors

Angiomyolipoma

Epithelioid angiomyolipoma

Medullary fibroma

Leiomyoma

Lipoma

Hemangioma

Lymphangioma

Other benign mesenchymal tumors

Leiomyosarcoma

Liposarcoma

Solitary fibrous tumor

Hemangiopericytoma

Fibrosarcoma and malignant fibrous histiocytoma

Rhabdomyosarcoma

Angiosarcoma

Osteosarcoma

Synovial sarcoma

Other malignant mesenchymal tumors

Lymphoid Tumors

Plasmacytoma

Metastatic Tumors

Tumor-Like Lesions

Xanthogranulomatous pyelonephritis

Inflammatory myofibroblastic pseudotumor

Perirenal and sinus cysts

References: Eble: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs (3rd Ed, 2004)

Suggested new features to incorporate: VEGF expression (Lab Invest 2008;88:962), gene expression (ScientificWorldJournal 2006;15;2505)

Angiomyolipoma (AML) - Kidney-tumor chapter

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Definition: neoplasm composed of thick walled vessels, smooth muscle and fat; includes spindle and epithelioid cells

Epidemiology: less than 1% of renal tumors, usually adults, either sporadic or associated with tuberous sclerosis (particularly if multiple masses), or with TSC2/PKD1 contiguous gene syndrome

Tuberous sclerosis: autosomal dominant neurocutaneous disorder in 1 per 6,000 to 11,000 individuals, of hamartomas / tumors of brain (subependymal giant cell tumor), retina, skin (cutaneous angiofibromas), heart (rhabdomyomas), bone, lung (lymphangioleiomyomatosis, multifocal micronodular pneumocyte hyperplasia) and kidney (angiomyolipoma in 40-80%, renal cell carcinoma [but some epithelioid tumors may be misclassified], cysts); also mental retardation and infantile / childhood seizures; caused by alterations of TSC1 gene (9q34, encodes hamartin) and TSC2 gene (16p13.3, encodes tuberin, which interacts with hamartin); 60-70% of cases are sporadic (OMIM #191100); patients with tuberous sclerosis present at younger age, tumors are usually larger and more often bilateral (Urology 2008;72:1077)

TSC2/PKD1 contiguous gene syndrome: both kidneys are enlarged and cystic, have classic angiomyolipomas and rare intraglomerular microlesions (Am J Surg Pathol 2002;26:198)

Pathophysiology: member of perivascular epithelioid cell (PEC) tumor family (Arch Pathol Lab Med 2001;125:751); related to lymphangioleiomyomatosis in lung; "sugar" tumor of lung, clear cell tumors of pancreas and uterus; tumors are neoplasms, not hamartomas; many cases have loss of heterozygosity of TSC2 gene; adipose tissue and smooth muscle cells are monoclonal but may arise independently (Am J Surg Pathol 2001;25:1231)

Clinical: characteristic radiologic appearance, benign behavior (almost always); also occurs in liver, where epithelioid smooth muscle cell component predominates

May coexist with renal cell carcinoma in non tuberous sclerosis patients, particularly clear cell carcinoma, which is HMB45 negative (Mod Path 2001;14:157)

CT scan images: same radiodensity as subcutaneous fat

Case reports: tuberous sclerosis patient with intraglomerular microlesions composed of smooth muscle and adipose cells (Hum Path 2000;31:1325), lung and pancreatic tumors metastatic to angiomyolipoma (Arch Pathol Lab Med 2008;132:1016), locally destructive tumor in tuberous sclerosis patient (Arch Pathol Lab Med 2005;129:676), liver invasion and lung metastases (Am J Surg Pathol 1991;15:1083), 21 year old post-partum woman with spontaneous tumor rupture (Arch Gynecol Obstet 2009 Feb 15 [Epub ahead of print])

Angiomyolipoma (continued)

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Treatment: tumors may be embolized (Eur Urol 2008 Apr 23 [Epub ahead of print]); also excision; rarely recurs locally; may cause death due to blood vessel invasion or retroperitoneal hemorrhage

Gross: red (vascular component), gray-white (smooth muscle component) and yellow (adipose component); resembles clear cell carcinoma, may invade local lymph nodes and renal vein even though benign (Arch Pathol Lab Med 1990;114:65); capsular invasion in 25%, tumors often multiple (1/3) and bilateral (15%); occasionally gross or microscopic cysts (Mod Pathol 2006;19:669)

Gross images:

solitary tumors - gray-white well circumscribed tumor; fatty tissue, necrosis and prominent vessels #1; #2; #3; variegated tumor #1; #2; tumor resembles yellow fat; tumor is composed predominantly of adipose; tumor compresses and distorts renal pelvis; tumor extends into main renal vein; massive intratumoral hemorrhage

multiple tumors - solid and hemorrhagic-cystic tumors; hemorrhagic tumor and smaller tumors; yellow tumor nodules in parenchyma and renal pelvis; gray tumor nodules in renal cortex

with other tumors - with clear cell renal cell carcinoma #1; #2; with renal cell carcinoma

Micro: triphasic with myoid spindle cells, islands of mature lipid-distended cells, dysmorphic thick walled blood vessels without elastic lamina; smooth muscle component appears to spin off from vessel walls and may be hypercellular, atypical, pleomorphic or epithelioid (see below); may resemble a high grade sarcoma if it metastasizes; also perivascular epithelioid cells with clear or eosinophilic cytoplasm, large hyperchromatic bizarre nucleus and possibly multinucleation, and intimate relationship with vessel wall; adipose tissue may be scanty; small mesenchymal nodules (< 2 cm) are precursors of angiomyolipoma (Mod Path 1996;9:1081); may have epithelial cysts (Am J Surg Pathol 2006;30:593, Mod Pathol 2006;19:669), prominent stromal sclerosis (Pathol Int 2008;58:306)

Angiomyolipoma (continued)

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Micro images:

triphasic tumor - adipose, smooth muscle and thick walled blood vessels #1; #2; #3; #4; #5; #6; #7; #8

other features - spindle cells with cigar shaped nuclei and granular cytoplasm; smooth muscle cells appear to arise from outer walls of blood vessels #1; #2; myomatous foci; tumor consists principally of smooth muscle; immature smooth muscle cells (leiomyoblasts) may be abundant; bizarre and atypical changes in smooth muscle component; tumor consists principally of adipose tissue; thick-walled blood vessels resembling arterialized veins are characteristic; abnormal tumor vessels may form aneurysms; trapped renal tubules; entrapped renal tubule has dilated to form a cyst; tumor largely replaces a renal hilar lymph node

with other tumors - clear cell carcinoma; pancreatic neuroendocrine carcinoma metastatic to angiomyolipoma; lung adenocarcinoma metastatic to angiomyolipoma

cystic tumors - epithelial lined cyst; cambium-like layer; cysts with AML type vessels; large and small cysts with prominent lymphatics; lymphatic rich smooth muscle; prominent lymphatics #1; #2; #3 (D2-40); #4 (D2-40); HMB45+ subepithelial cells; PR+ subepithelial cells

stains - melanocytic stains in various components; spindle cells are focally HMB45+; HMB45+; HMB45+; spindle cells are smooth muscle actin+; desmin+; S100+ (hepatic tumor); various stains #1 (liver/kidney tumors); #2

other - hepatic and renal tumors; tumor is present within liver parenchyma

Angiomyolipoma (continued)

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Cytology: oval to spindled cells and cohesive stromal fragments, adipose tissue and branching blood vessels in a hemorrhagic background; no mitotic figures (Cytopathology 2007;18:250)

Positive stains (in lipid distended, myoid and epithelioid cells): HMB45 (100%, Arch Pathol Lab Med 2002;126:49), MART-1/Melan-A, NKI/C3 (100%), muscle specific actin (HHF-35, 100%), calponin (100%), NKI-C3 (70%); also CD117 (Am J Surg Pathol 2002;26:493), desmin, estrogen receptor (20%, Am J Surg Pathol 1999;23:1011), HMB-50 (100%), microphthalmia transcription factor (50%, Am J Surg Pathol 2001;25:65), progesterone receptor (28%, usually women < age 50 with tuberous sclerosis), smooth muscle actin, tyrosinase (20-50%), vimentin; also evidence of lymphatic differentiation (podoplanin and D2-40, Hum Pathol 2009;40:374), S100 (fat component)

Note: HMB45 and MelanA are positive in fat > smooth muscle > blood vessel components (Arch Pathol Lab Med 2007;131:122)

Negative stains: keratin, renin

EM: premelanosomes

EM images: various images

Cytogenetics/molecular: 5q- (Hum Path 1999;30:295), monoclonal (Hum Path 1998;29:1063)

Differential diagnosis:

· leiomyoma - usually no prominent vascular or adipose component, negative for melanocytic markers

· leiomyosarcoma - prominent atypia, infiltrative, usually no prominent vascular or adipose component, negative for melanocytic markers

· melanoma - marked atypia, no prominent adipose or vascular component

· oncocytoma - oncocytes are prominent; no prominent adipose or vascular component, negative for melanocytic markers

· pleomorphic rhabdomyosarcoma - smooth muscle component is markedly atypical, tumor is infiltrative, no prominent adipose

or vascular component, negative for melanocytic markers

· renal cell carcinoma - usually marked atypia and infiltrative margins, not triphasic, negative for melanocytic markers

References: eMedicine

Cystic nephroma - Kidney-tumor chapter

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Definition: unilateral, solitary, multiloculated benign tumor with small non-communicating cysts containing clear colorless fluid; cysts have flat to hobnail epithelial lining

Also called multilocular renal cyst

Appears to be same disease but different morphology as mixed epithelial and stromal tumor (Am J Surg Pathol 2009;33:72, Am J Surg Pathol 2007;31:489, Arch Pathol Lab Med 2006;130:80)

Epidemiology: children less than 5 years old (usually boys) and adults ages 40-69 years (80%+ women)

Clinical: patients usually asymptomatic, may have abdominal mass or obstructive symptoms

Case reports: 16 month old boy (Radiographics 2004;24:589), 72 year old woman (Arch Pathol Lab Med 2001;125:828)

Treatment: benign; partial nephrectomy is recommended

Gross: large (5-10 cm), unilateral, solitary, multiloculated with non-communicating cysts 1-3 cm containing clear colorless fluid; sharply demarcated from adjacent kidney by thick fibrous capsule; surface is nodular

Gross images: multiple thin walled cysts #1; #2; tumor has multiple cystic structures which do not communication with each other or the renal pelvis; tumor of upper pole

Micro: cysts have flat to hobnail epithelial lining, no renal parenchyma within the cysts (so not polycystic disease), no poorly differentiated, blastemal or embryonal elements in stroma; may have hemorrhage; stroma may contain smooth muscle, skeletal muscle, cartilage or resemble ovarian stroma; rarely has immature blastema or abortive tubular elements resembling Wilms’ tumor; may have clear cells in lining epithelium, but no nests of clear cells in septa by definition (if present, call clear cell carcinoma)

Cystic nephroma (continued)

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Micro images: small and large cysts separated by thin fibrous septa #1; #2; #3; #4; cysts are lined by flattened epithelium #1; #2; cuboidal epithelial cells line the cyst; only mature elements are present in the septa; cysts are separated by septa of a distinctive type of fibrous connective tissue, with no renal nephron elements in septa; epithelial cells lining the cysts vary from flattened to low cuboidal or even columnar; occasional lining epithelial cells exhibit nuclear enlargement and hyperchromasia

case report - 72 year old woman - figure 1: MRI, T1 shows complex cystic mass of right kidney; fig 2: 14 cm, white-tan, bosselated tumor; fig 3: septa and solid areas have mature fibrous tissue; fig 4A: keratin+ cyst epithelium; 4B: vimentin+ stroma

stains - CK19+; CK19+; smooth muscle actin, ER, CD10, high molecular weight keratin

Cytology: sparse epithelial cells with moderate nuclear atypia (Acta Cytol 2008;52:91)

Positive stains: keratin in epithelium; vimentin and desmin in stromal cells

EM: cyst lining has long cilia and other features of collecting tubules

Differential diagnosis (children):

· Wilms’ tumor - must sample extensively to exclude blastema; has expansile solid regions of nephroblastomatous tissue not confined by cystic spaces

Differential diagnosis (adults):

· cystic renal cell carcinoma - has nests of malignant clear cells in septa

· lymphangioma - lined by D2-40+ endothelium, not keratin+ epithelium

References: eMedicine

Epithelioid angiomyolipoma (AML) - Kidney-tumor chapter

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Also called atypical AML, oncocytoid AML

Epithelioid component present in 8% of cases, with mean volume of 51% of tumor (Am J Surg Pathol 2009;33:289)

May include cases diagnosed incorrectly as renal cell carcinoma in tuberous sclerosis patients (Am J Surg Pathol 1998;22:180)

Clinical: may have aggressive behavior but rarely metastasize

Case reports: 28 year old man with malignant transformation (Am J Surg Pathol 2002;26:523), 44 year old woman (Arch Pathol Lab Med 2004;128:1176), 47 year old man with microhematuria (Arch Pathol Lab Med 2004;128:e19), 50 year old woman with lung and abdominal (Am J Surg Pathol 2000;24:889), 73 year old woman with kidney tumor initially called renal cell carcinoma (Hum Path 2000;31:516), malignant tumor arising in association with classic AML (Am J Surg Pathol 2001;25:121), two patients (Arch Pathol Lab Med 2002;126:610), two fatal cases (Arch Pathol Lab Med 1994;118:735)

Micro: predominance of epithelioid cells ranging from uniform polygonal cells with mild atypia to bizarre multinucleated straplike cells; usually nuclear atypia (93%), often mitotic figures (47%), coagulative tumor necrosis (27%); may have epithelioid giant cells; thin or thick hyaline cords may represent sclerosed vessels; often no recognizable fat, may lack characteristic vascularity; TSC related cases are more likely to have microscopic AML foci, epithelioid component and epithelial cysts (Am J Surg Pathol 2009;33:289)

Micro images: various images #1; #2; #3; whole mount shows well circumscribed solid tumor with no adipose tissue or thick walled vessels

44 year old woman with atypical epithelioid cells - figure 1: nonencapsulated but well demarcated tumor; fig 2: epithelioid cells with abundant clear to lightly eosinophilic granular cytoplasm, large pleomorphic vesicular nuclei, prominent eosinophilic nucleoli; fig 3: huge straplike cells with eosinophilic cytoplasm, multiple peripheral nuclei; fig 4: HMB45+

Epithelioid angiomyolipoma (AML) (continued)

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Virtual slides: epithelioid angiomyolipoma

Cytology: imprint shows large, atypical cells with abundant, round to polyhedral, granular cytoplasm; occasional intranuclear cytoplasmic inclusions, occasional bizarre, giant nuclei with hyperchromasia and huge nucleoli, occasional mitotic figures (Acta Cytol 2002;46:545)

Cytology images: smooth muscle and adipose tissue

Positive stains: HMB45, NCI-C3; Ki-67 (Int Urol Nephrol 2008 Oct 7 [Epub ahead of print])

Negative stains: AE1-AE3, CAM5.2, EMA, S100, desmin

Differential diagnosis:

· adrenocortical carcinoma - usually different location, often huge, may have normal adrenal gland component, negative for melanocytic markers

· melanoma - marked atypia, no prominent adipose or vascular component

· oncocytoma - no prominent adipose or vascular component, negative for melanocytic markers

· renal cell carcinoma - usually marked atypia and infiltrative margins, not triphasic, negative for melanocytic markers

· primary renal sarcoma - usually no prominent epithelioid component, negative for melanocytic markers

· sarcomatoid renal cell carcinoma - has residual renal cell carcinoma component, negative for melanocytic markers

References: Am J Surg Pathol 1997;21:1123, Am J Surg Pathol 1998;22:663

Fibroepithelial polyp of renal pelvis - Kidney-tumor chapter

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Rare; <50 cases reported; more common in ureter

Epidemiology: young adults with gross and painless hematuria; more common in women

Origin: considered mesodermal in origin

Xray: polypoid filling defect by intravenous pyelogram

Radiologic images: retrograde pyelography shows filling defect in left renal pelvis

Case reports: 57 year old woman with abdominal pain and microscopic hematuria (Arch Pathol Lab Med 1999;123:850)

Treatment: benign; local resection if causes obstruction

Gross: polypoid exophytic mass with smooth, glistening external surface and gray-white-pink cut surface

Gross images: large polyp almost completely fills renal pelvis

Micro: thick fibrous stalk and connective tissue core covered by urothelium; connective tissue core contains collagen, smooth muscle and blood vessels with edema and inflammatory cells

Micro images: urothelium covers fibrovascular tissue with loose stroma and small blood vessels

Negative stains: CD34

Differential diagnosis:

· angioma - vascular lesion, no fibrous stalks, no urothelial cells

· leiomyoma - smooth muscle cells, no fibrovascular stalks, no urothelium

· schwannoma - neural features, no smooth muscle cells, no fibrovascular stalks, no urothelium; S100+

Glomus tumor - Kidney-tumor chapter

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Definition: tumor of modified perivascular smooth muscle cells

Variants include glomus tumor, glomangioma (more vascular) and glomangiomyoma (has elongated smooth muscle cells)

Clinical: usually benign behavior; most common site is distal extremities, rare in visceral organs or kidney

Case reports: 55 year old woman with renal glomangioma (Arch Pathol Lab Med 2005;129:1172), 62 year old man #1 (Int J Surg Pathol 2009 Jan 28 [Epub ahead of print]), #2 (UPMC Case #602), three patients with solid glomus tumor, glomangioma and glomangiomyoma (Am J Surg Pathol 2007;31:585)

Micro: well circumscribed, sheets and nests of round and somewhat cohesive cells that may appear epithelioid; histologic appearance depends on vascular cell to glomus cell ratio, their differentiation, and the amount and composition of the stroma

Micro images: glomus tumor-various images; glomangioma-various images

Positive stains: smooth muscle actin, vimentin, type 4 collagen

Negative stains: negative for endothelial, epithelial, melanocytic and neuroendocrine markers, although some of these markers may stain vessels and entrapped renal epithelium; also negative for desmin

EM: modified smooth muscle cells

References: eMedicine

Hemangioma - Kidney-tumor chapter

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Definition: benign vascular lesion, either capillary, cavernous or mixed

Usually at tips of papillae; 10% are multiple

May cause recurrent hemorrhage

Small, so difficult to find

May clinical resemble cystic renal cell carcinoma (Int J Clin Oncol 2008;13:166)

Case reports: 22 year old woman with giant cavernous hemangioma (AJR Am J Roentgenol 2004;182:411), 40 year old woman with gross hematuria (Int Braz J Urol 2004;30:216)

Micro images: mixed capillary-cavernous hemangioma; massive cavernous hemangioma occupies much of renal medulla and pelvis; cavernous hemangioma of bladder

Inflammatory myofibroblastic tumor - Kidney-tumor chapter

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Also called inflammatory pseudotumor

Epidemiology: rare; median age 57 years, range 21-76 years; no gender preference; often asymptomatic

Case reports: 37 year old man and 54 year old woman (Arch Pathol Lab Med 2000;124:1209), 56 year old man (World J Surg Oncol 2007;5:106)

Treatment: nephrectomy; does not appear to recur (unless inadequate excision) or metastasize (Am J Surg Pathol 2003;27:658)

Gross: often involves renal pelvis and adjacent soft tissue or perirenal soft tissue; unencapsulated, partially circumscribed, 4-13 cm, composed of firm white tissue or myxoid/gelatinous; no hemorrhage, no necrosis

Gross images: polypoid lesion of renal pelvis and calyces

Micro: patterns are myxoid vascular (resembling nodular fasciitis or granulation tissue), compact spindle cell with aggregates of lymphocytes or plasma cells, or hypocellular fibrous with dense keloid-like fibrosis; composed of uniform, bland spindle cells and variable collagen, lymphocytes, plasma cells; occasionally has foam cells, osseous metaplasia or mild nuclear atypia; no/rare mitotic figures

Micro images: spindle cells and inflammatory cells in myxoid stroma; ill-defined spindle cell proliferation of renal pelvis; spindle cells in loose fascicular pattern; various images

stains - smooth muscle actin+; vimentin+, CD34

Positive stains: smooth muscle actin, HHF35, vimentin

Negative stains: ALK1, desmin, keratin, p53

Differential diagnosis:

· fibromatosis - culture-like fibroblasts, infiltrative border, usually no inflammatory infiltrate

· fibrous histiocytoma - storiform pattern of fibrohistiocytic cells, possibly giant cells

· spindle cell sarcoma - spindle cells exhibit atypia

Juxtaglomerular cell tumor - Kidney-tumor chapter

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Rare, <100 cases described

Origin: specialized smooth muscle cells of the wall of the glomerular afferent arteriole (juxtaglomerular apparatus)

Epidemiology: mean age 23-38 years, also children

Associated with severe uncontrollable hypertension due to excess renin production; rarely secretes inactive renin with controllable or no hypertension

Other renin producing tumors (usually with only rare renin producing cells) are renal cell carcinoma, Wilms’ tumor, mesoblastic nephroma, hepatoblastoma, lung carcinoma, pancreatic adenocarcinoma, ovarian and soft tissue tumors, glioblastoma multiforme

Treatment: nephron-sparing surgery is curative; blood pressure may normalize after excision (J Hypertens 2008;26:368), benign behavior with no/rare recurrences or metastases (AJCP 2001;116:854)

Case reports: 10 year old boy with severe hypertension (Am J Surg Pathol 1994;18:837), 25 year old woman with high plasma renin activity (Arch Pathol Lab Med 1993;117:1161), 27 year old woman (Arch Pathol Lab Med 2004;128:e112), 46 year old man with 15 cm tumor that invaded renal vein and metastasized to both lungs (Am J Surg Pathol 2004;28:1098), 2 cases with a dominant papillary pattern (Hum Path 1993;24:1168)

Gross: well circumscribed, solid, gray-white-yellow, solitary, up to 8 cm; may have small foci of hemorrhage or small cystic spaces; usually doesn’t invade beyond kidney

Micro: sheets, nodules, papillary structures or trabeculae of variably sized tumor cells with granular eosinophilic cytoplasm; round, oval, and spindled nuclei with frequent atypia; edematous microcystic foci; papillary structures may have flat/cuboidal lining cells and inner polygonal cells; also hemorrhage, mast cells, prominent thick-walled or delicate blood vessels; hemangiopericytoma-like vascular pattern, hyalinized stroma; rarely coagulative tumor necrosis, minimal mitotic activity

Juxtaglomerular cell tumor (continued)

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Micro images: sheets of cells with hemangiopericytoma-like vascular pattern #1; #2; organoid pattern; round or oval cells with abundant cytoplasm and vesicular nuclei and chronic inflammatory cells #1; #2; #3; epithelial cells with prominent granular cytoplasm; trabecular growth of uniform epithelioid cells in hemangiopericytoma-like vascular network; cells have granular cytoplasm and only mild pleomorphism; tumor (right) with adjacent clear cell carcinoma (left); various images

stains - renin granules are PAS+ diastase resistant

case reports - 27 year old woman - figure 1: 2 cm, solid, tan cortical mass; fig 2: solid, compact pattern of round/polygonal cells with focal papillary and tubular patterns; fig 3: cells have moderate cytoplasm, round central nuclei, little stroma present; fig 4: EM shows rhomboid, membrane bound renin protogranules with 6-10 nm periodic crystalline array, some with an electron dense zigzag pattern traversing the array

Positive stains: PAS, renin (strong and diffuse), renin RNA by ISH, vimentin, CD34 and CD117 (Arch Pathol Lab Med 2006;130:707); variable actin

Negative stains: HMB45, keratin, EMA

EM: rhomboid-shaped renin protogranules, secretory granules

EM images: rhomboid-shaped renin protogranules #1; #2

Cytogenetics: -9 and -11 (Hum Pathol 2008;39:459)

Differential diagnosis:

· metanephric adenoma - no papillary structures, no atypia, negative for PAS and renin

· papillary renal cell carcinoma - marked atypia, foam cells, negative for PAS and renin

Leiomyoma - Kidney-tumor chapter

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Usually incidental, 1-3 mm in cortex, rarely in capsule (Acta Radiol 2006;47:752)

Micro images: 57 year old woman (Histol Histopathol 2007;22:883)

Gross images: firm circumscribed tumor with a whorled cut surface

Micro: benign spindle cell proliferation

Micro images: well circumscribed lesion #1; #2

Positive stains: alpha smooth muscle actin, h-caldesmon, calponin, muscle actin, myosin and desmin

Differential diagnosis: angiomyolipoma - usually vascular and lipomatous components; positive for melanocytic markers

Lipoma - Kidney-tumor chapter

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Usually incidental, in cortex

Case reports: huge retroperitoneal mass (Br J Radiol 2006;79:e148)

Gross images: parapelvic lipomatosis; tumor appears to arise in hilar adipose tissue

Micro images: cortical tumor projects beneath the renal capsule

Differential diagnosis:

· angiomyolipoma - usually vascular and smooth muscle components; positive for melanocytic markers

· atypical lipomatous tumor of retroperitoneum - large tumor with hyperchromatic atypical nuclei

Lymphangioma - Kidney-tumor chapter

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Also called renal lymphangiectasia

Epidemiology: mean age 34 years, 60% female (J Urol 1977;118:22)

Case reports: 28 year old man with microscopic hematuria (Radiology 2001;219:442), Hum Path 1992;23:465

Gross: well circumscribed, multicystic

Gross images: large cystic lesion adjacent to renal pelvis; large intrarenal lesion has honeycomb appearance

Micro images: cysts lined by flattened endothelium

Differential diagnosis: multilocular renal cyst

Medullary fibroma - Kidney-tumor chapter

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Also called renomedullary interstitial cell tumor, renal hamartoma

Physiology: medullary interstitial cells regulate intrarenal blood flow, absorption of water and salt, and ultimately blood pressure through secretion of prostaglandins

Benign, usually found at autopsy (1 per 700 cases, Pol J Pathol 2008;59:21)

Gross: well circumscribed, gray-white firm nodule, < 1 cm, within pyramids

Gross images: multiple lesions in medullary pyramids #1; #2

Micro: fibroblast like cells, collagenous tissue and entrapped tubules at periphery

Micro images: fibroblast-like cells in myxoid or collagenous stroma #1; #2; circumscribed fibrogenic lesion among collecting tubules; small stellate cells, some with vacuolated cytoplasm; various images

Positive stains: Oil red O, Sudan black B

Negative stains: CD34

EM: resemble interstitial fibroblasts of kidney; large lipid droplets in cytoplasm

References: Hum Path 1972;3:559

Metanephric adenofibroma - Kidney-tumor chapter

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Definition: biphasic, circumscribed tumor with focal embryonal epithelium identical to metanephric adenoma and bland spindled stroma

Formerly known as nephrogenic adenofibroma

Rare; < 50 cases reported

Member of metanephric tumor family, including metanephric adenoma (purely epithelial) and metanephric stromal tumor (purely stromal)

Can merge with the morphology of Wilms’ tumor, supporting the concept that these are related lesions (Am J Surg Pathol 2001;25:433)

Epidemiology: mean age 14 years, range 2-35 years; associated with papillary renal cell carcinoma, polycythemia, hypertension which resolves after nephrectomy (Am J Surg Pathol 1992;16:325)

Treatment: benign, excision is curative, chemotherapy not needed

Gross: solitary, nonencapsulated, vaguely circumscribed, irregular or spherical firm mass with tan-gray-white-yellow cut surface; variable cysts

Gross images: solid and vaguely nodular tumor

Micro: well circumscribed, biphasic tumor with focal embryonal epithelium identical to metanephric adenoma and bland spindle cell stroma; also intratumoral angiodysplasia, concentric cuffing of entrapped tubules ("onion skinning") and heterologous differentiation; spans morphologic spectrum between benign pure stromal and pure epithelial lesions; epithelial cells are bland with no mitotic figures; entrapped tubules may have papillary hyperplasia; numerous psammoma bodies

Micro images: spindle and myxoid stroma with adenomatous foci are characteristic; foci resembling collecting duct carcinoma are seen in some lesions

Positive stains: epithelium (stains like metanephric adenoma) - keratin; stroma - vimentin, fibronectin, CD34 (often)

Negative stains: epithelium - EMA; stroma - actin, desmin

Differential diagnosis:

· mesoblastic nephroma - congenital myofibroblastic tumor with collagen; irregular infiltrating edges

· Wilms’ tumor-epithelial predominant - triphasic tumor with undifferentiated blastema

Metanephric adenoma - Kidney-tumor chapter

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Definition: pure epithelial tumor composed of embryonal-type epithelium with bland features

Rare, 0.2% of adult renal epithelial neoplasms; < 100 cases described

Also called metanephroid renal tumor, nephroblastoma-like adenoma of kidney, nephrogenic nephroma

First described in 1995 (Am J Surg Pathol 1995;19:1101)

Member of metanephric tumor family, including metanephric adenofibroma (mixed epithelial-stroma) and metanephric stromal tumor (purely stromal)

Epidemiology: mean 41 years but range is 5-83 years; 40-50% are incidental; 2/3 female; associated with polycythemia as a paraneoplastic syndrome in 12%

Typically benign

Origin: may arise from distal nephon/collecting duct; resembles developing metanephric tubular epithelium

May represent mature Wilms’ tumor as it resembles nephrogenic rests and maturing Wilms’ tumor histologically and immunohistochemically (Am J Surg Pathol 2001;25:1290), but 56% have changes at 2p13 not found in Wilms’ (Hum Path 2001;32:101)

Case reports: 7 year old girl with lung metastasis (Am J Surg Pathol 2000;24:570), 9 year old boy with multifocal tumor (Pathol Int 2009;59:49), 24 year old pregnant woman (Hum Pathol 2006;37:1227), 35 year old woman with passive seeding of hilar node (Arch Pathol Lab Med 2005;129:1317), 36 year old woman (Arch Pathol Lab Med 1999;123:1285), 44 year old woman (Arch Pathol Lab Med 2004;128:926), 54 year old woman (Mod Path 1996;9:329)

Gross: single, well circumscribed, non-encapsulated, tan-gray-white-yellow, solid/lobulated, mean 5 cm (range 0.3 to 15 cm); large tumors may have secondary cystic or hemorrhagic changes

Gross images: encapsulated tan tumor in lower pole (arrow)

Micro: small, uniform, closely packed tubules or papillae in loose stroma, composed of small cells with minimal cytoplasm, bland nuclei that may overlap, uniform chromatin, glomeruloid bodies, rare mitoses; may see hemorrhage, necrosis, calcifications (psammoma bodies), cysts; no atypia, no blastema, no/rare mitotic figures, no infiltrative growth, no vascular invasion

Metanephric adenoma (continued)

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Micro images: well circumscribed tumor #1; #2; small tubules composed of bland cells with uniform nuclei #1; #2; solid appearance due to tight packing of acini/tubules #1; #2; glomeruloid bodies; papillary pattern; psammoma bodies; various images; nodal involvement; uniform closely packed tubules composed of small cells with minimal cytoplasm and oval nuclei, also psammoma bodies

case report - 36 year old woman - figure 1: large, tan, fleshy tumor; fig 2: nests and tubules of small blue cells

case report - 44 year old woman - figure 1: well circumscribed tan firm nodule; fig 2: unencapsulated, hypercellular and basophilic staining tumor with pushing margin against normal kidney; fig 3: tumor composed of small tightly packed tubules with scant stroma and occasional calcifications; fig 4: tumor cells have scant cytoplasm, uniform nuclei, delicate chromatin, indistinct nucleoli;

comparison with other tumors - metanephric adenoma, papillary renal cell carcinoma and Wilms’ tumor; compared to papillary carcinoma-solid variant and metastatic thyroid insular carcinoma #1; #2

stains - CD57+; WT1+; AMACR-; CK7-

Metanephric adenoma (continued)

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Cytology: small, well differentiated epithelial tubules with bland nuclei, psammoma bodies (Cytopathology 2008;19:80, Acta Cytol 2007;51:468)

Positive stains: WT1 (strong/diffuse), CD57 (strong/diffuse), CK7 (focal), AE1 (focal), vimentin (solid areas)

Negative stains: AMACR (Mod Pathol 2006;19:218); also glycogen, CD56, desmin, NCAM, EMA

Molecular: no consistent abnormalities (Mod Path 2003;16:1060)

Molecular images: FISH shows 2 signals for #17 in most cells

EM: cilia on luminal side rest on abundant basement membrane

Differential diagnosis:

· metastatic insular thyroid carcinoma (Arch Pathol Lab Med 1999;123:415)

· papillary renal cell carcinoma (particularly solid variant) - red-brown with thick capsule, cells have more cytoplasm, nuclear grooves, prominent nucleoli; also foamy histiocytes, delicate vasculature; strong CK7, strong AE1, strong AMACR, EMA+, CD57-, WT1-, +7 and +17

· Wilms’ tumor - younger age, grossly tan-gray with hemorrhage or cysts, triphasic, WT1+, CD57-, vimentin-

Mixed epithelial and stromal tumor of kidney - Kidney-tumor chapter

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Definition: benign tumor with cystic and solid growth of benign mesenchymal and epithelial elements in ovarian-type stroma

First described in 1998 (Pathol Res Pract 1998;194:445)

Appears to be same disease but different morphology as cystic nephroma (Am J Surg Pathol 2009;33:72, Am J Surg Pathol 2007;31:489, Arch Pathol Lab Med 2006;130:80)

Also called cystic hamartoma of renal pelvis (Am J Surg Pathol 1993;17:1169) and adult mesoblastic nephroma (Am J Surg Pathol 1993;17:1029, Am J Surg Pathol 1998;22:827), although it lacks the genetic abnormalities of mesoblastic nephroma (Hum Path 2001;32:513)

Epidemiology: rare; almost exclusively perimenopausal women with obesity or receiving exogenous hormones, or men treated with lupron or DES (Am J Surg Pathol 2000;24:958).

Clinical: benign behavior

Case reports: 41 year old woman #1 (Arch Pathol Lab Med 1990;114:533), #2 in dialysis patient with bilateral tumors 5 years apart (Hum Pathol 2008;39:142), 53 year old woman with incidental cystic mass (Mod Path 1999;12:417), 58 year old man with no history of hormonal treatment (Urology 2008;71:168e7), 72 year old woman (Case of the Week #83), fat predominant tumor resembling angiomyolipoma (Int J Surg Pathol 2008;16:73), two cases with malignant transformation (Hum Pathol 2008;39:463), malignant tumor with rhabdoid differentiation (Hum Pathol 2007;38:1432)

Treatment: nephron-sparing surgery is recommended (Urology 2008;71:1142); does not recur or metastasize

Gross: in renal pelvis; well circumscribed but unencapsulated, mean 6 cm, range 3-12 cm, solid and cystic, yellow-tan

Gross images: multiloculated cystic tumor with smooth cyst lining; attached to renal pelvis by narrow pedicle

Micro: cystic and solid growth of benign mesenchymal and epithelial elements in ovarian-type stroma that contains smooth muscle, fibroblasts and myofibroblasts with embedded epithelial structures (tubules and cysts); cysts often have hobnailed epithelium; no blastema, no immature epithelial elements, no atypia

Classic: no hemorrhage, no necrosis, no/rare mitotic figures

Cellular: increased stromal cellularity, may have hemorrhage, necrosis, high mitotic index

Mixed epithelial and stromal tumor of kidney (continued)

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Micro images: image #1; #2; #3; spindled myofibroblastic stromal component with tubular elements; various images #1; #2 (fig 1/2); stromal predominant tumor #1; #2; AE1/AE3; ER; PR

Virtual slides: #1

Positive stains: epithelium - keratin, EMA, CEA, vimentin, stroma - alpha smooth muscle actin, desmin, vimentin, ER, PR

Negative stains: HMB45, CD34; stromal cells - AE1-AE3, EMA, S100

EM: spindle cells have mitochondria, ribosomes and submembranous condensations composed of clusters of filaments; also basement membrane, abundant collagen fibers, dense plaques, pinocytotic vesicles, nearly continuous external lamina; rare endoplasmic reticulum

Differential diagnosis:

· clear cell renal cell carcinoma - more than occasional clear cells

· leiomyoma (particularly stromal predominant tumors, Arch Pathol Lab Med 2005;129:910) - no epithelial elements except trapped normal tissue, no ovarian-type stroma, not cystic

· nephroblastoma / cystic partially differentiated nephroblastoma - blastema present

· metanephric adenofibroma or adenoma - children/young adults, cysts uncommon, spindle cells are actin-, desmin-

· sarcomatoid renal cell carcinoma - atypia, renal cell carcinoma component present, necrosis, mitotic figures

· solitary fibrous tumor - no epithelial elements, no ovarian type stroma, usually not cystic

Myelolipoma of kidney - Kidney-tumor chapter

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Usually in adrenal gland, < 50 cases elsewhere, <25 reported cases in kidney

Benign

Case reports: 65 year old man with hilar tumor (Arch Pathol Lab Med 2006;130:1049), 66 year old man with renal sinus tumor (Arch Pathol Lab Med 1999;123:631), 66 year old man with perirenal tumor (Arch Pathol Lab Med 1994;118:188)

Gross images: well delineated lesion (arrow) infiltrating into hilum

Micro: mixture of adipose tissue and normal hematopoietic cells; no bony spicules; not connected to medullary cavity of any bone by definition

Micro images: fat cells and hematopoietic cells; myelolipoma separated from renal parenchyma by fibrous band (arrow); various images

Oncocytoma - Kidney-tumor chapter

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Definition: benign tumor of uniform round/polygonal cells with abundant, intensely eosinophilic and granular cytoplasm with uniform small, round, central nuclei with evenly dispersed chromatin

4-7% of adult renal epithelial tumors

Origin: intercalated cell of collecting duct

Epidemiology: adults age 50+; 2/3 men; usually incidental; may coexist with renal cell carcinoma; rarely associated with renal failure due to multiple tumors or large bilateral tumors (Arch Pathol Lab Med 2002;126:648)

Birt-Hogg-Dube’ syndrome: rare, autosomal dominant syndrome of small dome-shaped papular fibrofolliculomas of face, neck and upper trunk; associated with multiple renal tumors (mean 5.3), usually chromophobe carcinomas or oncocytomas, oncocytosis, pulmonary cysts and spontaneous pneumothorax (Am J Surg Pathol 2002;26:1542), associated with 17p12q11 abnormality involving folliculin protein (Arch Pathol Lab Med 2006;130:1865)

Xray images: CT shows circumscribed and homogeneous tumor except for an irregular central zone which proved to be a central scar; MR shows same tumor with prominent central scar

Case reports: 56 year old man with bilateral renal oncocytosis (Arch Pathol Lab Med 2004;128:e177), 62 year old man (Arch Pathol Lab Med 2003;127:1229), involving ectopic and crossed fused kidneys (Arch Pathol Lab Med 2002;126:648), with clear cell carcinoma (Am J Surg Pathol 1998;22:271), with focal chromophobe carcinoma and metastasis (Int J Surg Pathol 2009;17:158), encased within fibrotic shell resembling retroperitoneal fibrosis (Arch Pathol Lab Med 1994;118:1026); multilocular cystic tumor (J Clin Pathol 2006;59:223)

Treatment: benign behavior if follow strict diagnostic criteria, even if degenerative atypia (Am J Surg Pathol 1997;21:871); excision is curative

Gross: well circumscribed, no capsule, solid, homogenous, mahogany or brown-yellow (same as cortex), 3-6 cm, stellate central scar in larger lesions; 5% are bilateral or multifocal; may invade renal capsule or renal vein, 20% have gross hemorrhage but necrosis is rare; gross appearance is an important criteria

Gross images: mahogany brown tumor has stellate central scar #1; #2; #3; #4; #5; light brown tumor with central scar #1; #2; well circumscribed mahogany brown tumor #1; #2; #3; tumor has two stellate scarred zones; central cystic change

Oncocytoma (continued)

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Micro: nesting, alveolar or tubular patterns (closely packed at periphery, more separated centrally) of uniform round/polygonal cells with abundant, intensely eosinophilic and granular cytoplasm, uniform small, round, central nuclei with evenly dispersed chromatin and smooth contour of nuclear membrane, occasional degenerative atypia (bizarre nuclear pleomorphism), focal vacuoles possible near areas of fibrosis; also “oncoblasts”-small cells with minimal cytoplasm and dense hyperchromatic nuclei; stroma is myxoid or hyalinized; occasionally cystic change, psammoma bodies, variably sized tubular structures, capsular / perinephric fat invasion (20%) or vascular invasion (5%); no papillary pattern (although may have small papillary fronds in areas of cystic change), no clear/spindle cells, no necrosis, no perinuclear halo; if mitotic figures in more than one 20x field, classify as eosinophilic chromophobe carcinoma

Note: grossly noted scar is composed of central loose stroma surrounded by closely packed nests of cells

Note: nuclear grading not needed since benign behavior (Am J Surg Pathol 1997;21:1)

Micro images: alveolar nests of cells with loose myxoid stroma #1; #2; #3; alveolar nests #1; #2; sheets of cells with abundant eosinophilic cytoplasm; cells have granular acidophilic cytoplasm and small, round, regular nuclei slightly less than 10 um; scarred zone has tumor cells separated by mature hyalinized fibrous connective tissue; incompletely differentiated oncocytes; various images

other patterns - cording; trabecular; tubulocystic #1; #2

other changes - focal degenerative atypia #1; #2; #3; osseous metaplasia; invasion of periphephric fat #1; #2; Birt-Hogg-Dubé associated tumors; multilocular cystic tumor

62 year old man - figures 1/2: nests of round to polygonal cells with abundant granular, eosinophilic cytoplasm and central round/oval nuclei; fig 3: EM shows abundant abnormal mitochondria with parallel cristae

bilateral renal oncocytosis with renal failure - various images

Oncocytoma (continued)

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stains - vimentin staining #1; #2; classic & eosinophilic variant of chromophobe carcinoma and oncocytoma, H&E and Hale’s colloidal iron; parvalbumin staining-G: positive (unusual); H: negative; EpCAM- (only focally positive) versus diffusely positive in chromophobe renal cell carcinoma

Cytology: large cells with homogenous granular cytoplasm, nuclei have no/mild nuclear membrane irregularities, tiny nucleoli, mild pleomorphism and only an occasional large, more hyperchromatic nucleus (Cancer 1999;87:161)

Cytology images: abundant granular cytoplasm and small, round and very regular nuclei #1; #2; small clusters and single cells with uniform cytoplasm; Diff-Quik shows homogeneous granular cytoplasm and round, regular nuclei without grooves

Positive stains: low molecular weight cytokeratin (CK 8/18, may be dot like), CK7 (may have intensely positive scattered cells in a background of negative staining cells), CK14 (strong), EMA, vimentin (focally positive in 73%, usually at edge of central scar or in small clusters scattered throughout the tumor, Arch Pathol Lab Med 2007;131:1782); also parvalbumin (calcium binding protein, Mod Path 2001;14:760), RON proto-oncogene (also in chromophobe renal cell carcinoma, Am J Surg Pathol 2004;28:1045), CD117/c-kit (Am J Surg Pathol 2004;28:676), E-cadherin, S100 (Hum Pathol 2006;37:462), kidney-specific cadherin (Am J Clin Pathol 2006;126:79)

Panels of markers to differentiate renal tumor subtypes:

(1) beta defensin1+, parvalbumin+, vimentin- in 100% (8/8) (small series, Am J Surg Pathol 2003;27:199)

(2) vimentin-(may be focally positive), GSTalpha-, EpCAM- (may be focally positive) (Arch Pathol Lab Med 2007;131:1290); second line markers are CD117+, CK7-

Negative stains: CK7 (may have focal positive cells), CK20 (variable), Sudan fat stain, Hale’s colloidal iron (may be positive at luminal surface in tubular areas), RCC-MA (Am J Surg Pathol 2001;25:1485), N-cadherin, CD10 (usually), low Ki-67 labeling index (Mod Path 1998;11:1115)

Oncocytoma (continued)

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EM: marked increase in mitochondria, predominantly uniform and round with stacked parallel (lamellar) cristae, which causes the eosinophilia; few microvesicles in the apical portion of the cytoplasm, rare short and stubby microvilli; no/rare other organelles, lipid, glycogen, microvilli, brush border (Am J Surg Pathol 2000;24:1247)

EM images: cytoplasm is packed with large mitochondria #1; #2

Cytogenetics / molecular: chromosome 1 abnormalities in 88% of bilateral tumors versus 28% of single tumors (Arch Pathol Lab Med 2007;131:81, Am J Clin Pathol 2008;129:377); mt-DNA mutations are common (Hum Mol Genet 2008;17:986)

FISH images: loss of chromosome 1

Differential diagnosis:

· chromophobe carcinoma, eosinophilic variant - diffuse, solid growth but no nesting pattern; has distinct, thickened cell border; wrinkled nuclei with binucleation, perinuclear halos, mitotic figures, diffusely and strongly positive for Hale’s colloidal iron, microvesicles by EM

· clear cell carcinoma with granular cytoplasm - compact alveolar growth pattern; also hemorrhage, necrosis and frequent mitotic figures, long microvilli by EM, 3p-

References: eMedicine

Oncocytosis

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Definition: diffuse renal involvement by numerous oncocytic lesions without necrosis, may be hemorrhagic

Rare; usually is at least 1 dominant nodule (2-10 cm), usually an oncocytoma, may be a chromophobe carcinoma or a hybrid

43% bilateral

Case reports: 45 year old woman with 11 tumors, all with normal appearing chromosomes (Mod Pathol 2008;21:498), 53 year old with > 100 tumors causing end stage renal disease (Arch Pathol Lab Med 2001;125:683)

Gross images: bilateral renal oncocytosis; kidney contained nine discrete tumors

Micro: multiple oncocytic nodules, often hybrid nodules with chromophobe carcinoma; oncocytes may infiltrate between benign glomeruli and tubules; often diffuse oncocytic change in nonneoplastic tubules, benign oncocytic cortical cysts

Micro images: small nodule; various images #1; #2

References: Am J Surg Pathol 1999;23:1094

Papillary adenoma - Kidney-tumor chapter

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Commonly found at autopsy: 10% at age 21-40 years, 40% at age 70-90

Increasing numbers during life are being detected with more widespread whole body imaging

Associated with long term hemodialysis, acquired cystic disease (in 1/3)

Multiple adenomas associated with papillary renal cell carcinoma (Hum Pathol 2007;38:239)

Classification (WHO 2004):

Clearly benign: 0.5 cm or less, tubulopapillary architecture

Probably benign: same as “clearly benign” but up to 1 cm

Likely malignant: < 1 cm with solid growth pattern or clear cells

Malignant: 1 cm or more

References: Adv Urol 2008:974848

Case reports: 44 year old man with incidental lesion (Case of Week #43)

Gross: usually 5 mm or less, in cortex, encapsulated, yellow-gray

Gross images: small, well circumscribed cortical mass; 1.5 cm subcapsular tumor; adenoma is 8 cm, but has benign histology and is non-invasive

Micro: usually papillary; also tubular or tubulopapillary; cells have scant amphophilic to basophilic cytoplasm, round/oval nuclei with stippled to clumped chromatin and indistinct nucleoli; variable nuclear grooves, no/rare mitotic figures

Classified as type 1 (basophilic) or type 2 (eosinophilic), based on criteria for papillary renal cell carcinoma

Note: small tumors of clear cells are considered to be small renal cell carcinomas, clear cell type, with malignant potential

Micro images: circumscribed but nonencapsulated tumor; small cortical lesion; tiny tumor has papillary architecture; tubular structures lined by cuboidal cells with small nuclei; xanthoma cells in stroma; incidental tumor #1; #2; #3; type 1 (basophilic) tumors; figure A: type 1, fig B: type 2

Cytogenetics: gains of #7, 17, 16, 12 and 20 and loss of Y occur early in papillary renal cell neoplasia (Mod Path 2003;16:1053)

Cytogenetic images: figure A-single Y present in normal tubules; fig B-gain of #12 (3 signals) in papillary adenoma

Pelvic lipomatosis - Kidney-tumor chapter

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Definition: overgrowth of normal fat in renal pelvis

Note: term also used for overgrowth of normal fat in perivesicle and perirectal spaces (i.e. true pelvis)

Associated with chronic pyelonephritis and renal lithiasis

Usually most prominent in renal hilum

Gross images: renal pelvic fat that clinically resembled malignancy

Differential diagnosis: lipoma

Perineurioma - Kidney-tumor chapter

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Definition: benign tumor of perineurial cells; very rare in kidney

Case reports: 7 year old girl (Gen Diagn Pathol 1997;143:75), 26 year old man (Ann Pathol 2002;22:476), 66 year old woman (Arch Pathol Lab Med 1993;117:654)

Micro: storiform proliferation of delicate spindle cells with elongated processes; no long fascicles, no ectatic vessels

Micro images: site unknown (not kidney) - spindled tumor may resemble myxofibrosarcoma; delicate spindle cells with elongated processes; EMA+

Positive stains: EMA, type 4 collagen

Negative stains: S100

EM images: thin perineurial cell cytoplasmic processes with prominent pinocytotic vesicles

Differential diagnosis:

· low grade fibromyxoid sarcoma - focal to diffuse whirling, heavily collagenized stroma with abrupt transition to myxoid areas, often epithelioid areas, large collagen rosettes, infiltration of adjacent tissue

· schwannoma - long fascicles, ectatic blood vessels, S100+, EMA-, type 4 collagen-

Post-kidney transplant tumors - Kidney-tumor chapter

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See also Lymphomas: non B cell chapter for discussion on post-transplant lymphoproliferative disorders

Tumors can be of donor origin (glioblastoma multiforme-Hum Path 1993;24:1256, lymphoma-Hum Path 1991;22:1291) or due to immunosuppression

Risk for cancers due to immunosuppression is 1.9; in Italian study, most common are viral related Kaposi’s sarcoma and EBV+ non-Hodgkin’s lymphoma, with common sites being native kidney, uterus and liver (Epidemiol Prev 2008;32:205); in Thailand study, most common are urothelial and hepatocellular carcinomas (Transplant Proc 2008;40:2403)

Also increased risk of skin cancers (Br J Dermatol 2006;154:498)

Hodgkin’s lymphoma: 2% of post-transplant lymphomas, mean 4 years after transplant; usually males; case report at Arch Pathol Lab Med 2001;125:1480; typical staining of Reed-Sternberg cells is CD15+, CD30+, EBER+, negative for B and T cell markers, micro images

Non-Hodgkin lymphoma: well recognized risk post-transplant, usually EBV associated extranodal B cell lymphomas that respond to reduction of immunosuppressive treatment; EBV promotes proliferation of B cells, which may escape T cell control

Post-transplant lymphoproliferative disorders: plasmacytic and polymorphic B cell hyperplasias are not monoclonal by flow cytometry; most B cell lymphomas or myelomas are clonal by flow cytometry, even if genotypic studies are negative (AJCP 2002;117:24); Reed-Sternberg-like cells are usually CD20+, EBV+, CD30+ but CD15- (Hum Path 1997;28:493)

Case reports of post kidney transplant tumors (not in kidney): bladder urothelial carcinoma, polyoma virus+ (Br J Cancer 2008;99:1383), Kaposi’s sarcoma in 5 year old boy (Hum Path 1992;23:956), plasmacytoma in tonsil (Arch Pathol Lab Med 2004;128:e76), T cell lymphoma (Am J Surg Pathol 1993;17:1046), T cell lymphoma of vulva (Am J Surg Pathol 1993;17:842)

Treatment: reduction in immunosuppression usually not sufficient for tumors in general, also need chemotherapy (Acta Haematol 2008;120:36)

Schwannoma - Kidney-tumor chapter

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Definition: benign tumor of Schwann cells

Also called neurilemoma

Very rare, <20 cases reported in kidney through 2000

Epidemiology: mean age 47 years, range 18-84 years, usually asymptomatic (Mod Path 2000;13:851)

Treatment: resection is curative (Mod Pathol 2008;21:779)

Gross: renal pelvis or intrarenal; well demarcated, yellow-tan, smooth, bulging, mean 10 cm; compresses adjacent renal parenchyma

Gross images: yellow-tan lobulated intrarenal mass; multinodular masses of yellow-tan tissue with central cysts or softening

Micro: well circumscribed, often primarily cellular subtype (predominantly Antoni A pattern), may have myxoid and hypocellular areas (Antoni B); may have degenerative nuclear atypia (ancient schwannoma features), aggregates of foamy macrophages

Micro images: circumscribed and encapsulated, no infiltration; Antoni A areas with fascicular growth pattern, thick walled blood vessel and scattered lymphocytes; Antoni B area, hyalinized and dilated blood vessel; aggregates of foamy macrophages; various images and stains; strongly S100+

Positive stains: S100

Negative stains: cytokeratin, CD57/Leu7, smooth muscle actin, desmin, CD34

Differential diagnosis:

· angiomyolipoma - triphasic with blastema and epithelioid component

· sarcoma - spindle cells plus nuclear pleomorphism and nuclear atypia, infiltrative margins

· sarcomatoid carcinoma - marked atypia and renal cell carcinoma usually present, infiltrative margins, keratin+

Sinus histiocytosis with massive lymphadenopathy - Kidney-tumor chapter

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Also called Rosai-Dorfman disease

Case reports: 13 year old boy #1 with large, asymptomatic renal mass with adjacent hilar adenopathy (Arch Pathol Lab Med 1985;109:867), #2 with 10 year clinical course of extensive involvement of multiple organ systems, leading to death (Arc